Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:26]1[CH:27]=[C:28]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1F
Temperature: 120 °C
Yield: 25.6 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 90 mg, 0.261 mmol), 3-Fluoro-4-methoxyphenylboronic acid (89 mg, 0.522 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 21 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.5 mL of 1,4-dioxane and 1 mL of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 120° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (55-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (29 mg, 26%). 1H NMR (DMSO-d6) δ: 11.18 (s, 1H), 7.82-8.28 (m, 5H), 7.61 (d, 2H), 7.43 (t, J=8.8 Hz, 1H), 6.39 (s, 1H), 5.19 (s, 1H), 3.97 (s, 3H), 2.42 (s, 3H), 1.46 (s, 6H). ESI-MS: m/z 435.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N

Procedure:
10% Palladium-on-carbon (0.035 g) was added to a stirred solution in methanol (40 ml) of the nitro compound so obtained. (0.28 g) and the mixture was stirred at ambient temperature under 1 atmosphere pressure of hydrogen. After uptake of hydrogen had ceased, the catalyst was removed by filtration and the filtrate was evaporated to give N-(3-amino4-methylphenyl)-3-morpholinobenzamide; NMR Spectrum: (DMSOd6) 2.0 (s, 3H), 3.19 (t, 4H), 3.78 (t, 4H), 4.8 (s, 2H), 6.8 (q, 2H), 7.08 (s, 1H), 7.1 (d, 1H), 7.34 (m, 2H), 7.4 (s, 1H), 9.8 (s, 1H); Mass Spectrum: M+H+ 312.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C@:14]12([CH3:24])[C:20]([CH3:22])([CH3:21])[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH2:23].N1C=CC=CC=1>O>[C@:14]12([CH3:24])[C:20]([CH3:21])([CH3:22])[C@@H:17]([CH2:18][CH2:19]1)[CH2:16][C@@H:15]2[NH:23][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC1(C)C2CC[C@@]1(C)C(N)C2
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)[C@H]2CC[C@@]1(C)[C@@H](NC(=O)c1cnc3ccccc3n1)C2
Yield: 50.3 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (R)-(+)-bornylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 140 mg (50%) of (150):
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[C:8]([O:12][C:13](=[O:39])[NH:14][C:15]([CH3:38])([CH3:37])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[CH:20][C:19]=1[NH2:36])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13](=[O:39])[NH:14][C:15]([CH3:38])([CH3:37])[CH2:16][N:17]1[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:36]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(CNc1c(N)cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
Ethoxyacetyl chloride (3.5 mL, 32.0 mmol) was added to a solution of tert-butyl[2-(3-amino-6-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (12.71 g, 29.1 mmol) and triethylamine (8.1 mL, 58.2 mmol) in approximately 250 mL of anhydrous dichloromethane. After stirring for 2 hours, the volatiles were removed under reduced pressure and the resulting brown residue was dissolved in ethanol, followed by the addition of 8.1 mL of triethylamine. The reaction was heated at reflux for 2.5 days and then cooled to ambient temperature. The solvent was removed under reduced pressure and dichloromethane was added. The solution was sequentially washed with aqueous sodium bicarbonate (2×) followed by brine; dried over sodium sulfate; filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 0-15% CMA in chloroform to provide 8.4 g of tert-butyl[2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate as an orange foam.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12]>C(Cl)(Cl)Cl>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Brc1nc2ccccc2s1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNc1nc2ccccc2s1

Procedure:
2-Bromo-1,3-benzothiazole (505.5 mg, 2.36 mmol) and N-(2-aminoethyl) carbamic acid tert-butyl ester (1.1356 g, 7.10 mmol) were stirred in a preheated oil bath (125° C.) for 5 h. The solid mass was dissolved in chloroform, and the resulting solution was washed with aqueous sodium bicarbonate then dried, filtered and concentrated to a yield a residue. The residue was purified by flash chromatography, eluting with 60% ethyl acetate in hexane to yield tert-butyl 2-(benzo[d]thiazol-2-ylamino)ethylcarbamate as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: CC(=O)C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 119 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (369 mg, 2.09 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (500 mg, 2.3 mmol) in AcCN (7.5 mL) was added DIPEA (0.41 mL, 2.3 mmol). After stirring at room temperature for 5 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give tert-butyl (3R,4R)-4-(6-chloro-5-cyanopyrazin-2-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (880 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([OH:29])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:34]COC(C)=O.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([O:29][CH3:34])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 250 mg (0.578 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 35) in MeOH (3 mL) was added thionyl chloride (78.0 μl, 1070 μmol) dropwise at 0° C. After being stirred at 25° C. for 14 h, the reaction was diluted (EtOAc), basified (sat NaHCO3), extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:22][CH2:23][O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)(=O)=O.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:23][O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCC2)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(OCCOC3CCCC3)cc2)cc1

Procedure:
A solution of 24 g (0.12 mol) of 4-benzyloxyphenol in 100 cc of DMF is added dropwise to a 50% suspension of 6.2 g (0.132 mol) of NaH in 50 cc of DMF. When the evolution of gas has ended, a solution of 36 g (0.127 mol) of 2-cyclopentyloxyethyl tosylate in 100 cc of DMF is then added. The mixture is stirred for half an hour. It is then heated for 2 hours at 55°-60° C. with stirring. The reaction mixture is poured into iced water. Extraction is carried out with diethyl ether. The ether phase is washed with dilute sodium hydroxide solution and then with water, dried and evaporated to dryness.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]1=2.[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:2][CH2:3][O:4][CH:5]2[C:12]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=3[O:10][CH2:9][O:8][C:7]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]2=3)=[CH:33][CH:34]=1)[CH3:24]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: Clc1ccc2c(c1)C(OCCBr)c1cc(Cl)ccc1OCO2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3cc(Cl)ccc3OCOc3ccc(Cl)cc32)cc1)OCC
Temperature: 60 °C
Yield: 52.9 %

Procedure:
To a solution of 12-(2-bromo-ethoxy)-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene (404 mg, 1.0 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in dry toluene (6 mL) was added potassium carbonate (276 mg, 2.0 mmol) and 18-crown-6 (528 mg, 2.0 mmol). The mixture was heated at 60° C. for 16 h. The mixture was filtered, and concentrated in vacuo. The residue was submitted to flash chromatography using toluene/ethyl acetate (19:1) as eluent to give 297 mg (53%) of the title compound; 1H NMR (300 MHz, CDCl3) δ1.18 (t, 3H), 1.25 (t, 3H), 2.96 (d, 2H), 3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.90-3.95 (m, 2H), 4.0 (t, 1H), 4.15-4.25 (m, 4H), 4.55 (d, 1H), 5.87)d, 1H), 6.18 (s, 1H), 6.88-6.95 (m, 4H), 7.10-7.25 (m, 4H), 7.60 (d, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:29])[O:27][CH3:28]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:26]([O:27][CH3:28])=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 107.4 %

Procedure:
Methyl 2-phenylpiperidine-4-carboxylate (4.33 g, 19.75 mmol) was dissolved in DCM (150 mL) and DIPEA (3.78 mL, 21.72 mmol), then methyl carbonochloridate (1.710 mL, 21.72 mmol) was added. The solution was stirred at room temperature for 1 h 45 min. More DIPEA (1.720 mL, 9.87 mmol) and methyl carbonochloridate (0.777 mL, 9.87 mmol) were added and the reaction continued at room temperature for another 30 min. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-phenylpiperidine-1,4-dicarboxylate (5.88 g, quant.) as a yellow oil. MS m/z 278 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=1[Cl:12])[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.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>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:14])[C:6]=1[Cl:12])[CH3:2]
Reactant: CCOC(=O)c1ccnc(Cl)c1Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccnc(C)c1Cl

Procedure:
A mixture of 2,3-dichloroisonicotinic acid ethyl ester (3.15 mmol), K2CO3 (4.73 mmol) and trimethylboroxine (3.15 mmol) in 4 mL dioxane was degassed with Ar. Then, tetrakis(triphenylphosphine)palladium (0.31 mmol) was added and the mixture was heated to reflux overnight. At RT, the reaction mixture was poured into water and extracted with DCM. The combined organic layers were dried over K2CO3, filtered over a pad of celite and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (8/2) gives the desired product as brown oil;
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)=[O:29])=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: O=C(c1ccc(O)cc1)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3cccc4ccccc34)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A wag treated with (4-Hydroxy-phenyl)-naphthalen-1-yl-methanone from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C30H28O6 [M+NH4]+: 507, [M+H]+485.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:4](=[O:13])[N:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH:10]1([CH2:9][N:5]2[CH:6]=[C:7]([F:8])[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])=[N:3][C:4]2=[O:13])[CH2:12][CH2:11]1
Reactant: Nc1nc(=O)n(CC2CC2)cc1F
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc(=O)n(CC2CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
4-Amino-1-(cyclopropylmethyl)-5-fluoropyrimidin-2(1H)-one (200 mg, 1.09 mmol) was dissolved in CH2Cl2 (0.90 mL) and pyridine (172.4 mg, 2.18 mmol) at room temperature and then was cooled to −20° C. Ethyl chloroformate (166 mg, 1.53 mmol) was then added to the reaction mixture dropwise, keeping the reaction temperature between −20 and −5° C. After the addition was complete, the reaction was allowed to warm slowly to room temperature and stirred for 2 h. The reaction mixture was filtered, and the solids were rinsed with EtOAc (15 mL×3). The filtrate was concentrated in vacuo, and purified by preparative thin layer chromatography, to afford ethyl 1-(cyclopropylmethyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-ylcarbamate (70 mg, 30%) as a pale yellow solid: mp 90-92° C.; 1H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.70 (d, J=7.2 Hz, 2H), 1.24-1.36 (m, 4H), 0.65-0.57 (m, 2H), 0.46-0.39 (m, 2H); ESIMS m/z 256 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([SH:24])([CH3:23])[CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:24][C:21]([CH3:23])([CH3:22])[CH3:20])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)(C)S
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=O
Temperature: 110 °C
Yield: 104.8 %

Procedure:
A mixture of 3-bromo-2-fluoro-5-nitro-benzaldehyde (1.0 g, 4 mmol), potassium carbonate (667 mg, 4.8 mmol) and 2-methyl-2-propanethiol (326 mg, 0.40 mL, 3.6 mmol) in dry DMF (5 mL) was heated at 110° C. in a sealed tube for 16 h. The reaction was cooled to RT, water was added, and the mixture extracted with dichloromethane (2×30 mL). The combined organic fractions were washed with water (3×15 mL), dried over sodium sulfate, filtered and concentrated to afford 1.2 g of the crude title compound, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]>CN(C=O)C.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccnc1
Reaction time: 64 h
Yield: 102.1 %

Procedure:
3-Hydroxypyridine(2.83 g, 29.83 mmol) was dissolved in DMF (70 mL), the solution was cooled in an ice bath, NaH (1.3 g, 32.81 mmol) and N-(3-bromopropyl)phthalimide (8 g, 29.83 mmol, Aldrich) were added, the ice bath was removed, and the reaction mixture was stirred for 64 hours. The reaction was diluted with CH2Cl2 and filtered through celite to give a 1:1 mixture of N- and O-alkylated products. Recrystallization from EtOH afforded a 4:1 mixture of N- and O-alkylated products. The mother liquor was taken up in water and extracted with CH2Cl2, then the organic layer washed with water (5x) to afford the desired N-(3-(3-pyridyloxy)propyl)phthalimide (8.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.ClC1C=C([F:25])C=CC=1CC#N.ClC1C=C(F)C=CC=1C>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:25])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: N#CCc1ccc(F)cc1Cl
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Agent: Cc1ccc(F)cc1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc(F)cc1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 15 from 2-chloro-4-fluorophenylacetonitrile, which was itself prepared from 2-chloro-4-fluorotoluene (Aldrich, mp. 238° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:28]=2)O1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[N:31]1([CH2:30][CH2:29][N:27]2[CH:28]=[C:24]([C:2]3[CH:3]=[N:4][C:5]([C:8]4[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=4)=[N:6][CH:7]=3)[CH:25]=[N:26]2)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: OCc1cccc(-c2ncc(-c3cnn(CCN4CCOCC4)c3)cn2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, 2.82 g (10 mmol) of [3-(5-bromopyrimidin-2-yl)-phenyl]methanol are dissolved in 100 ml of ethylene glycol dimethyl ether, 3.38 g (10 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl}morpholine and 4.25 g (20 mmol) of tripotassium phosphate trihydrate are added. The reaction mixture is evacuated twice and flushed with argon. 840 mg (1.2 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, the mixture is again evacuated and flushed argon. The reaction mixture is stirred at 80° C. for 16 hours. The reaction mixture is diluted with dichloromethane and water and filtered through Celite. The organic phase is separated off, washed with water again, the organic phase is dried over sodium sulfate and evaporated to dryness. The residue is recrystallised from isopropanol; yield: 2.74 g, LCMS: 366 (M+H).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[N+:11]([C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])([O-])=O>C1COCC1>[CH:1]([NH:11][C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:2]
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1NC=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
A solution of formic acid (0.02 mL, 0.56 mmol) and acetic anhydride (0.05 mL, 0.56 mmol) was heated to 50° C. for 2 hours under an argon atmosphere. The resulting mixture was diluted with THF (0.2 mL) and added dropwise to a solution of 34B (50 mg, 0.19 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The resulting solution was concentrated to dryness and purified by chromatography (SiO2, 40% EtOAc in hexane) to afford 44A (58 mg, 100%).