Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7](O)[CH2:6][CH2:5]2.C1C=CC(OP(OC2C=CC=CC=2)([N:21]=[N+:22]=[N-:23])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOC(C)=O>[N:21]([C@H:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[N+:22]=[N-:23]
Reactant: O[C@H]1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1CCc2cc(Br)ccc21
Temperature: 15 °C
Yield: 83.5 %

Procedure:
A solution of (S)-5-bromo-indan-1-ol (15.0 g, 70.4 mmol) in toluene (150 mL) was cooled in an ice bath under N2 and was treated with diphenylphosphoric azide (DPPA, 22.0 g, 91.5 mmol) in one portion followed by 1,8-diazabicyclo[5,4,0]undec-7-ene (15.0 g, 98.6 mmol). The reaction temperature was kept between 3 and 10° C. during 3 hours of addition and the mixture was warmed to 15° C. over the next hour (TLC indicated no starting material). The mixture was diluted with EtOAc (300 mL) and was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to give a dark oil. The crude product was purified by silica gel column (packed with 1% Et3N in hexanes, hexane eluant) to give (R)-1-azido-5-bromo-indane (14 g, 83%) as an oil which was used directly in the next step.
Reaction SMILES: [CH2:1]([N:6]1[C:11](=[O:12])[CH:10]2[CH2:13][C:8]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)([CH2:9]2)[C:7]1=[O:23])[C:2]([CH3:5])([CH3:4])[CH3:3].C(OCC)C>C(OCC)(=O)C.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:8]23[CH2:9][CH:10]([CH2:13]2)[C:11](=[O:12])[N:6]([CH2:1][C:2]([CH3:4])([CH3:3])[CH3:5])[C:7]3=[O:23])=[CH:19][CH:18]=1
Reactant: CC(C)(C)CN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)CN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 4.1 g of 3-neopentyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 80 ml of ethyl acetate, hydrogenated in the presence of 0.4 g of 5% palladium-on-carbon and worked up. Melting point 141.5°-143° (from diethyl ether).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15](=O)[CH2:16][C:17](=O)[CH3:18])[C:9]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:8]1=2)=[O:6])([CH3:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[NH2:56][NH2:57]>CCO>[F:35][C:32]([F:34])([F:33])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1)[CH2:21][N:14]([C:15]1[CH:16]=[C:17]([CH3:18])[NH:57][N:56]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C:8]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:9]1=2
Reactant: NN
Reactant: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Solvent: O
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(C(=O)OC(C)C)c3cc(Cl)ccc32)n[nH]1
Temperature: 0 °C
Yield: 21.2 %

Procedure:
Add cold (ice bath) absolute EtOH (1 mL) slowly to a cooled 0° C. stirred mixture of (+/−)-5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (118 mg, 0.20 mmol) and phosphorus pentoxide (511 mg, 3.6 mmol). Then, add hydrazine hydrate (0.062 mL, 2.0 mmol) dropwise while keeping the mixture cooled at 0° C. Heat at 100° C. overnight in a sealed tube. Cool down the mixture and remove the solvents under reduce pressure. Partition the residue between water and dichloromethane. Separate the layers, and dry organic phase over anhydrous magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, and then by a SCX cartridge to afford the title compound (25 mg, 21%). MS (ES+): 589 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=O)[N:7]2[CH3:12].C(Cl)(=O)C(Cl)=O.COC1C=CC=C2C=1C=C(C(Cl)=O)N2C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([B:44]2[O:52][C:49]([CH3:51])([CH3:50])[C:46]([CH3:48])([CH3:47])[O:45]2)=[CH:40][C:39]=1[O:53][CH3:54]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl.Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([B:44]3[O:45][C:46]([CH3:47])([CH3:48])[C:49]([CH3:51])([CH3:50])[O:52]3)=[CH:40][C:39]=1[O:53][CH3:54])=[O:15])[N:7]2[CH3:12]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COc1cccc2c1cc(C(=O)O)n2C
Agent: CN(C)c1ccncc1
Agent: COc1cccc2c1cc(C(=O)Cl)n2C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To 4-methoxy-1-methyl-1H-indole-2-carboxylic acid (24.4 mmol, 5 g) and oxalyl chloride (24.4 mmol, 2.3 mL) in dichloromethane (60 mL) N,N-dimethylformamide (1.22 mmol, 95 μL) was added and the mixture was stirred at room temperature until it formed a clear solution (approximately 4 hours). The mixture was concentrated in vacuo. The residue, 4-methoxy-1-methyl-1H-indole-2-carbonyl chloride, was added to a solution of 4-amino-3-methoxyphenylboronic acid pinacol ester (24.2 mmol, 6.03 g) and 4-dimethylaminopyridine (2.419 mmol, 0.296 g) in pyridine (30 mL) and dichloromethane (30 mL). After stirring at room temperature overnight the reaction mixture was diluted with dichloromethane and 2N hydrochloric acid. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo to yield 10.55 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([NH:21][CH2:22][C:23]2[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])=[O:20])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:6]=2[N:7]=1.[CH3:32][C:33]1([CH3:50])[CH2:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][C:35]([CH3:49])([CH3:48])[NH:34]1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.O.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>[CH3:29][C:28]1[CH:27]=[C:26]([CH3:30])[NH:25][C:24](=[O:31])[C:23]=1[CH2:22][NH:21][C:19]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:6]=2[N:7]=[C:2]([C:37]2[CH2:36][C:35]([CH3:49])([CH3:48])[NH:34][C:33]([CH3:50])([CH3:32])[CH:38]=2)[CH:3]=1)=[O:20]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)c2ccccc2)c(=O)[nH]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
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: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C(C)c2ccccc2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.26 g, 0.54 mmol), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.172 g, 0.649 mmol.) and Pd(PPh3)4 (0.062 g, 0.054 mmol) in 1,4-dioxane (3 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 (0.206 g, 1.94 mmol.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by prep. HPLC to give the desired compound (12% yield). LCMS 539.20 (M+1)+; HPLC: 97.09% (@ 254 nm) (Rt; 5.747); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.84 (t, 1H, J=5.2 Hz), 8.73-8.64 (m, 2H), 8.36 (s, 1H), 7.86 (s, 1H), 7.34-7.21 (m, 5H), 6.84 (s, 1H), 6.30 (q, 1H, J=6.8 Hz), 5.89 (s, 1H), 4.38 (d, 2H, J=5.2 Hz), 2.88-2.77 (m, 2H), 2.23 (s, 3H) 2.12 (s, 3H), 1.95 (d, 3H, J=7.2 Hz), 1.56 (s, 6H), 1.46 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:8](C=O)=[CH:9][CH:10]=1)=[O:4].[C:23](O)(=O)[CH2:24][C:25]([OH:27])=[O:26].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:8]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1ccc(C=O)c(-c2cccc(C(F)(F)F)c2)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C=CC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The compound of step 3 of example 428 (400 mg, 1.30 mmol), malonic acid (262 mg, 2.52 mmol) and piperidine (16 mg, 0.19 mmol) were dissolved in pyridine (0.7 ml) and stirred in reflux for 1 h. The material was partitioned between 2N hydrochloric acid and ethyl acetate (product is only sparingly soluble). The combined organic extracts were dried over sodium chloride and evaporated to dryness to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH3:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[C:14](=[O:23])[C:13]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]([OH:20])[C:18]([CH3:21])([N:15]2[C:14](=[O:23])[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:12]([CH3:11])[O:17][CH2:16]2)[CH3:22])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)c2cc(F)cc(F)c2)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.4 %

Procedure:
3,5-Difluorobromobenzene (2.9 g) was added to a suspension of magnesium (0.41 g) in tetrahydrofuran, under an inert atmosphere at 20° C., slowly, to initiate reaction, then at a rate to maintain gentle reflux. After refluxing for 1 hour, the mixture was added to a solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (2.59 g) in tetrahydrofuran at -78° C. The solution was warmed to ambient temperature and stirred for 18 hours. Ammonium chloride and ethyl acetate were added and the organic phase dried (magnesium sulphate) and evaporated to give 1-(3,5-difluorophenyl)-2-methyl-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-propan-1-ol (1.32 g), m.p. 87.6-89.0° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)=[O:18].O>CN(C)C=O>[CH3:3][C:2](=[CH2:4])[C:1]([O:6][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:27][CH2:26]2)[CH2:23][CH2:24]1)=[O:18])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: CCCCCC1CCC(C2CCC(C(=O)OCCCCCCBr)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOC(=O)C1CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methacrylic acid (3.6 g, 41.8 mmol) in dimethylformamide (30 ml) is added dropwise to an ice cooled slurry of sodium hydride (60% suspension in paraffin oil) (1.5 g, 37.5 mmol) in dimethylformamide (50 ml). Once addition is complete, the mixture is allowed to warm to room temperature and is stirred for 1 h, the intermediate 4′-pentyl-bicyclohexyl-4-carboxylic acid 6-bromo-hexyl ester (15.0 g, 33.8 mmol) in dimethylformamide (100 ml) is added dropwise. The mixture is stirred at 50° C. over night. The mixture is cooled to room temperature, poured into icy water, and this is extracted three times with DCM. The DCM solution is washed with brine, water and then dried over sodium sulphate. The solution is evaporated to dryness and recrystallised from acetonitrile to afford a white waxy solid. Further purification is achieved by preparative HPLC using water/acetonitrile as eluant.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([CH:57]2[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]2)[CH:54]=[CH:53][C:52]=1[NH2:64]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:64][C:52]4[CH:53]=[CH:54][C:55]([CH:57]5[CH2:58][CH2:59][N:60]([CH3:63])[CH2:61][CH2:62]5)=[CH:56][C:51]=4[O:50][CH3:49])=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: COc1cc(C2CCN(C)CC2)ccc1N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (100 mg, 0.289 mmol) and N,N-Diisopropylethylamine (0.202 mL, 1.16 mmol) in 3.0 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (113 mg, 0.318 mmol). After stirring at room temperature for 30 minutes, 2-Methoxy-4-(1-methyl-piperidin-4-yl)-phenylamine (84 mg, 0.36 mmol) was added. The reaction mixture was heated at 65° C. overnight. The reaction was conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using 500:12:8 DCM:MeOH:7N NH3/MeOH as the eluant. The collected fractions afforded N-tert-Butyl-3-{2-[2-methoxy-4-(1-methyl-piperidin-4-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide as a yellow solid (19.66 mg, 11%). MP 189-198° C. LCMS (E/I+) 549.21 (M+H). 1H NMR (DMSO-d6)-9.01 (s, 1H), 8.56 (s, 1H), 8.35 (d, 1H, J=7.88 Hz), 7.99 (d, 1H, J=8.56 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.69 (t, 1H, J=7.82 Hz), 7.62 (s, 1H), 7.23 (d, 1H, J=4.72 Hz), 7.01 (d, 1H, J=4.76 Hz), 6.94 (s, 1H), 6.92 (s, 1H), 3.87 (s, 3H), 2.96-2.83 (m, 2H), 2.28-2.17 (s, 3H), 2.10-1.94 (m, 2H), 1.80-1.58 (m, 3H), 1.32-1.21 (m, 1H), 1.12 (s, 9H).
Reaction SMILES: [Zn:1].[F:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C@@H:9]([OH:29])/[CH:10]=[CH:11]/[C:12]#[C:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C@@H:18]([OH:28])[C@@H:19]([OH:27])[CH2:20][O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:5][CH:4]=1.O>CO>[Zn:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C@@H:9]([OH:29])/[CH:10]=[CH:11]/[CH:12]=[CH:13]\[CH:14]=[CH:15]\[CH:16]=[CH:17]\[C@@H:18]([OH:28])[C@@H:19]([OH:27])[CH2:20][O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:30][CH:31]=1
Reactant: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C=C\C=C\[C@H](O)COc1ccc(F)cc1
Yield: 10.8 %

Procedure:
Activated zinc was prepared from 10 g of zinc and the reduction carried out using the procedure described in Helv. Chim. Acta (1987), Vol. 70, p. 1025). A solution of (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester, (0.8 g, 1.2 mmol) in methanol (4 mL) was added to a slurry of activated zinc in 1:1 methanol:water (45 mL). The flask was stirred vigorously under nitrogen for 24–60 hours. The mixture was filtered through a pad of Celite 545 and rinsed with methanol (3×25 mL). Purification by chromatography on a reverse phase semi-prep column using a gradient of acetonitrile and water afforded 55 mg of (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid, methyl ester, as an oil; 1H-NMR (400 mHz, methanol-d4) δ 3.62 (m, 2H), 3.75 (s, 3H), 3.93 (m, 2H), 4.13 (m, 3H), 4.58 (m, 1H), 5.85 (m, 2H), 6.14 (m, 2H), 6.36 (m, 2H), 6.77 (m, 1H), 6.96 (m, 5H) ppm.
Reaction SMILES: [CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)(=[O:39])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)C2CCCC2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)(=O)C2CCCC2)cc1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of methyl 4-(2-cyclopentylsulfinylamino-5-trifluoromethylphenoxymethyl)benzoate (305 mg; prepared in Reference Example 33.) in methylene chloride (4.0 ml), meta-chloroperbenzoic acid (456 mg) was added at 0° C. The mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure to give the title compound (317 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:13]=[C:12](I)[C:11]3[CH:15]([CH3:18])[CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH3:27].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:13]=[C:12]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH3:27])[C:11]3[CH:15]([CH3:18])[CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1
Reactant: Cc1cnccc1N
Reactant: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(I)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1C(C)CC2
Temperature: 80 °C
Yield: 95.5 %

Procedure:
To a solution of 2-(5-chloro-2-fluorophenyl)-4-iodo-5-methyl-6,7-dihydro-5H-cyclopentapyrimidine (275 mg, 0.71 mmol, 1 eq) in dioxane (5 ml) was added Pd(OAc)2 (8 mg, 0.04 mmol, 0.05 eq) followed by BINAP (33 mg, 0.05 mmol, 0.075 eq), 4-amino-3-picoline (84 mg, 0.78 mmol, 1.1 eq) and Cs2CO3 (347 mg, 1.06 mmol, 1.5 eq). The reaction mixture was heated to 80° C. for 15 h. The reaction mixture was cooled to rt and filtered through Celite® and the crude material was purified by flash column chromatography (1:1/ethyl acetate:hexane-100% ethyl acetate) to afford [2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(3-methyl-pyridin-4-yl)-amine, 43 (250 mg, 96%).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].O>C(Cl)(Cl)Cl>[Br:2][CH2:3][CH2:4][NH:5][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromoethylamine hydrobromide (120.0 g) in chloroform (1400 ml) was added triethylamine (204 ml), and thereto was added dropwise benzyl chloroformate (100 ml) under ice-cooling slowly. The mixture was stirred at 0° C. for one hour, and warmed to room temperature, and further stirred overnight. To the reaction mixture was added water, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and dried under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give the title compound (110 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([F:16])[CH:8]=1)(=O)=O.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1.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]>[CH:19]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([F:16])[CH:8]=2)[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CC2)cc1F
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 91.7 %

Procedure:
A mixture of 3-fluoro-4-nitrophenyl trifluoromethanesulfonate (7.15 g, 24.73 mmol), cyclopropylboronic acid (2.55 g, 29.67 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexed with dichloromethane (1:1) (1.62 g, 1.98 mmol), and 2M cesium carbonate in water (19.8 mL, 39.56 mmol) in toluene (39.5 mL) was degassed for 20 min. The reaction mixture was stirred at 90° C. under N2 for 2.5 h. The reaction was cooled to RT, diluted with ethyl acetate (200 mL), and filtered through a pad of Celite. The filtrate was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified via flash column chromatography eluted with 0 to 75% DCM/hexane to give 4.11 g (91.7%) of 4-cyclopropyl-2-fluoro-1-nitrobenzene as an oil. 1H NMR (400 MHz, MeOD) δ 7.98 (dd, J=10.2, 6.6 Hz, 1H), 7.12-7.02 (m, 2H), 2.11-1.97 (m, 1H), 1.20-1.11 (m, 2H), 0.89-0.82 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC.O>COCCOC>[CH3:9][N:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:8]
Reactant: Cc1cc[nH]c(=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: COCCOC
Product: Cc1ccn(C)c(=O)c1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a suspension of 4-methy-2(1H)-pyridone (5 g, 45.82 mmol) and potassium carbonate (12.64 g, 91.64 mmol) in DME (100 mL) was added iodomethane (50.5 g, 366 mmol) at room temperature and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, poured into water (200 mL) and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine solution (200 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography on a Biotage (40 m) column to afford 2.5 g (44% yield) of 1,4-dimethyl-2(1H)-pyridone as an amorphous white solid. FAB-HRMS m/e calcd for C7H9NO (M+H) 123.0241. found 123.0246. b) Preparation of 1,4-dimethyl-3-iodo-2(1H)-pyridone and 1,4-dimethyl-5-iodo-2(1H)-pyridone