Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:43])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[C:28]([O:27][CH3:26])=[N:29][CH:30]=[C:31]([CH3:43])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 120 °C
Yield: 54 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 120° C. for 20 minutes under microwave irradiation. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (49 mg, 72%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 2.10 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1O)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2.P(Br)(Br)([Br:19])=O>>[Br:19][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1ccc2ncc(Cl)c(O)c2c1
Product: COC(=O)c1ccc2ncc(Cl)c(Br)c2c1
Temperature: 130 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A mixture of methyl 3-chloro-4-hydroxyquinoline-6-carboxylate (600 mg) and phosphoryl bromide (868 mg) was heated under stirring in an oil bath at 130° C. for 6 hours. Ice-water was added, followed by neutralization with saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain methyl 4-bromo-3-chloroquinoline-6-carboxylate (426 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].[C:13]([N:17]1[C:21]([NH2:22])=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].CS(O)(=O)=O>C(O)C>[C:13]([N:17]1[C:21]2=[N:22][C:7]([C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])=[N:25][C:23](=[O:24])[C:20]2=[CH:19][NH:18]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCCOc1ccccc1C=O
Reactant: CC(C)(C)n1ncc(C(N)=O)c1N
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2n(C(C)(C)C)[nH]cc-2c(=O)n1
Yield: 21.9 %

Procedure:
A mixture of 2-propoxybenzaldehyde (3.0 g, 18.27 mmol), 1-tert-butyl-5-amino-1H-pyrazole-4-carboxamide (2.5 g, 13.7 mmol), methanesulfonic acid (0.2 ml) and xylenes (50 ml) was refluxed overnight. The reaction mixture was stripped to dryness, treated with ethanol and again stripped to dryness. The residue was partitioned between chloroform and 10% KHCO3, the layers were separated, and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined, and concentrated in vacuo and the residue was dissolved in CH2Cl2 (30 ml) and combined with silica gel (20 g). The preloaded silica gel was placed on a silica gel column and eluted with 70% ether/hexanes, followed by ether (100%) to afford 0.98 g (22%) of 1-tert-butyl-6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one 1/100 hydrate, m.p. 130-131° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31](Cl)[N:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([NH:25][C@H:23]([C:14]2[N:13]([C@H:11]3[CH2:12][C@@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:10]3)[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH3:24])[N:30]=[CH:29][N:28]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
A mixture of (S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (50 mg, 0.15 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (23 mg, 0.15 mmol) and DIPEA (0.13 mL, 0.74 mmol) in IPA (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM then MeOH and then 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (50 mg, 75%). LCMS (Method B): RT 3.11 min [M+H]+ 458. 110185004
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21]CC)=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CCO.O>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([OH:21])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a solution of ethyl 2-(4-(benzyloxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (100 mg, 0.24 mmol) in EtOH (5 mL) was added an aqueous solution of lithium hydroxide (20.1 mg, 0.48 mmol) in water (1 mL). The reaction mixture was stirred at room temperature overnight and acidified with 1 N HCl to pH=3. The resulting mixture was extracted with EtOAc (15 mL) and combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (17 mg, yield: 18%). 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.29 (s, 1H), 8.56 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.44-7.34 (m, 5H), 7.06 (d, J=19.2 Hz, 2H), 5.50 (d, J=8.8 Hz, 1H), 5.172 (m, 5H), 3.2 (d, J=15.6 Hz, 1H), 2.18-2.11 (m, 1H). MS (ESI) m/z=393 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=2[C@:13]([C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)([OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=2[C@:13]([C@@H:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)([OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH2:3][CH2:2]1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCNC1
Yield: 42.5 %

Procedure:
A solution of (R)-tert-butyl 3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (120 mg) in 20% TFA/CH2Cl2 (20 mL) was stirred at 0° C. for 5 min. The solvent was neutralized by addition of sat'd aq NaHCO3, and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and evaporated to give the crude product. LC-MS analysis of the crude product indicated the presence of two isomers (10:1). The crude product was purified by reverse phase prep HPLC to afford the major isomer, (S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (40 mg, 42%). 1H NMR (400 MHz, CD4O): 0.36 (m, 2H), 0.63 (m, 2H), 0.86 (m, 1H), 1.55-1.11 (m, 1H), 1.82 (m, 1H), 2.29 (m, 2H), 2.45 (m, 1H), 2.66 (t, 1H), 2.94 (d, 1H), 3.24 (s, 3H), 3.31 (m, 2H), 3.91 (m, 2H), 6.98 (m, 2H), 726 (m, 1H). MS (E/Z): 366 (M+1). In addition, 2-fluoro-6-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)phenol was isolated as a byproduct.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.[Li+].[I-].Cl>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: Oc1ccc(C#Cc2ccccc2)cc1

Procedure:
A procedure similar to that described1 was used. A sample of 1-methoxy-4-(phenylethynyl)-benzene (0.4 g, 1.9 mmol) was added collidine (3 mL), LiI (1.5 g) and the solution heated under reflux for 5 h (>95% conversion). The solution was poured into water acidified with HCl, extracted with ether (3×50 mL) and dried (MgSO4). The ether was evaporated and the residue chromatographed (PE) eluting the title compound 0.3 g (80%): mp 125°-128° C. (cyclohexane) (lit2 mp 91°-92°C., lit3 mp 83°-84° C.); 1H NMR (300 MHz, DMSO-d6) δ 6.80 (d, J=8.77 Hz, 2H, C2H), 7.37 (d, 2H, C3H), 7.35-7.42 (m, 3H), 7.46-7.50 (m, 2H), 9.92 (s, 1H, OH); 13C NMR (300 MHz, DMSO-d6) δ 87.32 (acetylenic C), 89.98 (acetylenic C), 112.42 (sp2C), 115.74, 122.90 (sp2C), 128.20, 128.66, 131.06, 133.00, 158.06 (COH); IR (CDCl3) 3596 (OH), 3066 (w), 3039 (w), 2217 (w, acetylenic stretch), 1605, 1512, 1429 (w), 1328 (w), 1261 (s), 1219, 1171 (s), 1140 (w), 1099 (w), 834, 805 (w) cm-1. MS (EI) m/e 194 (M+, 100), 165 (29.4), 97 (11.3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].Cl.[NH2:22][C@@H:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:24][OH:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:27]([F:30])([F:29])[CH2:26][C@H:23]([NH:22][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])[CH2:24][OH:25]
Reactant: N[C@H](CO)CC(F)(F)F
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccnc(-n2nc(C(=O)N[C@H](CO)CC(F)(F)F)c3c2[C@@H]2C[C@@H]2C3)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (50 mg, 0.188 mmol), (S)-2-amino-4,4,4-trifluorobutan-1-ol hydrochloride (33.7 mg, 0.188 mmol), and triethylamine (0.052 mL, 0.376 mmol) in DMF (2 mL) was added HATU (71.4 mg, 0.188 mmol). The mixture was stirred at 23° C. for 30 min and purified by HPLC followed by preparative TLC to give the title product (6 mg) as a white solid. LCMS m/z=392.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.24-1.29 (m, 2H), 2.26-2.32 (m, 1H), 2.54-2.69 (m, 2H), 2.77-2.82 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.01 (dd, J=16.7, 6.4 Hz, 1H), 3.87 (d, J=4.0 Hz, 2H), 4.34-4.42 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.41 (dd, J=5.1, 1.1 Hz, 1H), 8.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[N+:33]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[NH2:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a of 8.6 g of an iron powder, 27 ml of acetic acid and 2.7 ml of water was added dropwise a solution of 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 23 ml of acetic acid, while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 2 hours, then, the reaction solution was filtrated through Celite and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel column chromatography to obtain 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:46][C:47](=[O:51])[C@H:48]([CH3:50])[NH2:49])C>CCOCC>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:49][C@H:48]([C:47]([OH:51])=[O:46])[CH3:50])=[O:11])=[CH:13][CH:14]=2)=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCC#Cc2ccc(Cl)cc2)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of 4-[N-trifluoroacetyl-13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the N-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}alanine as a white, crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Yield: 39.3 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ortho-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through celite®, and the filtrate was concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[O:11].Cl>C1COCC1.O>[Br:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH2:2][C:1]#[N:3])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(Br)c1
Temperature: 75 °C
Yield: 92.1 %

Procedure:
Acetonitrile (21.86 mL, 419 mmol) was added to a stirred suspension of 60% NaH (7.25 g, 181 mmol) in THF (150 mL). Then, methyl 3-bromobenzoate (30 g, 140 mmol) was added and the mixture was heated at 75° C. for 4 h. After cooling to room temperature, water followed by 1N HCl (200 mL) was added and the mixture was extracted with ethyl acetate (500 mL), washed with sat .NaHCO3 solution (200 mL), dried (Na2SO4), filtered and concentrated to afford 3-(3-bromophenyl)-3-oxopropanenitrile (29 g, 129 mmol, 93% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.09 (t, J=1.7 Hz, 1H), 7.90-7.86 (m, 1H), 7.83 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 4.08 (s, 2H).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C[Si](Cl)(C)C.C(=[N:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]([NH2:33])=[O:32])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CS(C)=O>[NH2:25][C:26]1[N:27]=[CH:28][N:29]([CH2:1][C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)[C:30]=1[C:31]([NH2:33])=[O:32]
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Reactant: COc1ccc(CO)cc1OC
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Cn2cnc(N)c2C(N)=O)cc1OC
Yield: 62.6 %

Procedure:
A dimethyl sulfoxide solution of 4.29 ml (30 mmol) veratryl alcohol (3,4-dimethoxybenzyl alcohol) was treated in 22.86 ml (180 mmol) trimethylsilyl chloride at room temperature for 1 hour. The resulting product was dissolved in ethyl acetate, washed with distilled water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under vacuum, the resulting residue was reacted with 2.14 g (10 mmol) of 4-benzylideneamino-5-imidazole carboxamide and 5.52 (40 mmol) of potassium carbonate in the same manner as in Reference Example 2 to obtain 1.73 g of 4-amino-1-(3,4-dimethoxybenzyl)-5-imidazolecarboxamide (yield 63%).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[CH3:32][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:26]([F:29])([F:27])[F:28])=[O:9]
Reactant: O=C(Nc1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of N,4-diphenyl-8-(trifluoromethyl)quinoline-3-carboxamide, (0.150 g, 0.382 mmol), whose preparation is described in Example 368, in DMF (20 mL) is added sodium hydride (0.010 g, 0.421 mmol). After stirring in an ice bath for 1 h, methyl iodide (0.027 mL, 0.421 mmol) is added drop wise and the reaction mixture is removed from the ice bath and stirred 2 h. The reaction mixture is partitioned between ethyl acetate and water and the aqueous layer is extracted with ethyl acetate. The combined extracts are washed with water, brine, and dried with magnesium sulfate. The extracts are concentrated and the residue is chromatographed with 1:4 ethyl acetate:hexanes to afford the title compound as a white solid (0.147 g, 96%). mp 188-190° C.; MS (ESI) m/z 407; HRMS: calcd for C24H17N2F3O+H, 407.13712; found (ESI, [M+H]+), 407.1361.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
An amount of 1.36 mL (14.14 mmol) of pyridin-2-yl-methanol is dissolved in N,N-dimethylformamide (10 mL) and cooled to 0° C., addition of 678.72 mg (28.28 mmol) of sodium hydride followed. The reaction mixture is kept at 0° C. for 1.5 hours. 1-Fluoro-4-nitrobenzene 1.5 mL (14.14 mmol) is subsequent added and stirred at room temperature overnight. 100 mL of water is added to the mixture and stirred for 10 more mins. The precipitate is filtered and washed many times with water. The white solid is re-dissolved in methylene chloride extracted three times with brine, dried over darko and magnesium sulfate, and evaporated to give the desired product as a white solid 2.7 g (85% yield); mp: 116-117° C.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>ClCCl>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35](=[O:36])[NH:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To the product from Example 88A (4.2 g, 9.8 mmol) dissolved in dichloromethane (100 mL) was added pyridine (1.62 mL, 20 mmol) followed by the dropwise addition of 2,2,2-trichloroethyl chloroformate (2.29 g, 10.8 mmol). The resultant solution was stirred for 4 hours and then concentrated under vacuum. The mixture was then poured into water (200 mL), the pH of the solution adjusted to 5 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried to provide the title compound (6.0 g, 100%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:18])(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)(Cl)Cl>[Cl:2][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:18]
Reactant: O=C(CCC(=O)c1ccccc1)OCc1cccc(Oc2ccccc2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CC=C(Cl)c1ccccc1)OCc1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a refluxing mixture of phosphorus pentachloride (5.8 g) and carbon tetrachloride (25 ml) is slowly added m-phenoxybenzyl 3-benzoylpropionate (5 g) in carbon tetrachloride (10 ml) over about 45 minutes. Refluxing is continued about 0.5 hr and then the reaction is poured onto ice and extracted with ether. The ether extracts are combined, washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried over calcium sulfate and solvent evaporated. The product is subjected to prep. TLC using 12% ethyl acetate/hexane and the major band collected to yield m-phenoxybenzyl 4-chloro-4-phenyl-3-butenoate.