Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]([S:13][CH3:14])=[C:4]([C:10](=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25].O>C(O)C>[CH2:8]([O:7][C:5]([C:4]1[C:3]([S:13][CH3:14])=[N:25][N:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[C:10]=1[CH3:11])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(C(C)=O)=C(SC)SC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1C
Yield: 56.4 %

Procedure:
A mixture of 1.22 g (5.23 mmol) of ethyl 3,3-bismethylthio-2-acetylacrylate and 1.11 g (5.23 mmol) of 2,4,6-trichlorophenylhydrazine in 12 mL of ethanol was heated at reflux for 2 hours. The cooled reaction mixture was then poured into cold water and the product was extracted into ether. The ethereal extracts were dried and evaporated and the residues were chromatographed on silica gel using 6:1 hexane/ethyl acetate as eluent to give 1.12 g (56%) of the desired product as a crystalline solid, m.p. 95-98° C. 1H-NMR (CDCl3) δ1.38 (3H, t, J=7), 2.30 (3H, s), 2.49 (3H, s.), 4.31 (2H, q, J=7), 7.47 m(2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[BH4-].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH3:14])=[O:4]
Reactant: COC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1Cc2ccccc2N1C
Reaction time: 8 h

Procedure:
A solution of methyl-1-methylindole-carboxylate* (6.0 g) in trifluoroacetic acid (50 ml) is cooled in an ice bath as sodium borohydride pellets (6.0 g) are added slowly, keeping the temperature below 10° C. The slurry is allowed to rise to room temperature and then stirred overnight. The unreacted sodium borohydride is decomposed with 50% sodium hydroxide and the mixture is extracted several times with ether. The extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to dryness to obtain an orange oil. This is distilled in a kuegelrohr (b.p.=128-150/0.2 mm) to yield colorless liquid, methyl-2, 3-dihydro-1-methylindole-carboxylate.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:18]=2)=[N:6][C:7]([Cl:12])=[C:8]([CH2:10][CH3:11])[N:9]=1)(=[O:3])[NH2:2].C(OCC)(=O)C.C(OC(=O)C)C.Cl>C(O)C>[Cl:12][C:7]1[N:6]=[C:5]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][C:8]=1[CH2:10][CH3:11]
Reactant: CCc1nc(C(N)=O)c(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2cnn(C3CCNCC3)c2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a mixture of tert-butyl 4-{4-[(3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino]-1H-pyrazol-1-yl}piperidine-1-carboxylate (1.69 g), ethyl acetate (10 mL), and ethanol (10 mL) was added a 4 M hydrogen chloride ethyl acetate solution (20 mL), followed by stirring at room temperature for 2 hours. The mixture was subjected to liquid separation by the addition of a 1 M aqueous sodium hydroxide solution and chloroform. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 5-chloro-6-ethyl-3-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (1.32 g) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1.Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CC(C)([O-])C.[Na+]>CO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: Brc1ncccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(-c2ncccn2)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 25.8 %

Procedure:
A mixture of (4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)boronic acid (0.349 g, 1.00 mmol), 2-bromopyrimidine (0.175 g, 1.10 mmol) and sodium tert-butoxide (0.106 g, 1.10 mmol) are suspended in a mixture of MeOH/1,4-dioxane (1 mL/2 mL). The suspension is purged with N2 before adding 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (41 mg, 5 mol %). The reaction is heated to 90° C. for 18 h. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is triturated with MeCN and DCM to give 99 mg of [4-(1H-Benzimidazol-2-yl)piperidin-1-yl][4-(pyrimidin-2-yl)phenyl]methanone.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:35])[C@@H:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:33][C:27]1[C:26]([CH3:34])=[C:25]([NH:24][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:35])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
To a 100 mL round bottom flask was added 4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-chloro-4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methyl benzonitrile (586 mg, 0.9 mmol, 1.0 equiv.) and 60 mL of anhydrous THF. The solution was cooled to −78° C. and TBAF (1 mL, 0.99 mmol, 1.1 equiv., 1M in THF) was added dropwise via a syringe. The solution was stirred for 3 h while the temperature was kept below −30° C. The reaction was quenched with 25 mL of saturated ammonium chloride and diluted with 25 mL of EtOAc. The layers were separated and the organic layer was washed with distilled water (1×25 mL) and brine (1×25 mL). The organic layer was dried over Na2SO4 and was concentrated in vacuo to yield an off-white solid. The product was purified via automated flash chromatography (0→50% EtOAc/hexanes→100% EtOAc, 24 g of silica gel; TLC Rf=0.43, 100% EtOAc, vanillin stain) to provide the desired product as a white solid (239 mg, 63% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.92 (d, J=2.15 Hz, 1H), 7.80 (dd, J=2.15, 8.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.79 Hz, 1H), 5.87 (d, J=8.79 Hz, 1H), 5.02 (dd, J=5.66, 8.79 Hz, 1H), 4.51 (m, 1H), 2.36 (s, 3H), 1.41 (d, J=6.45 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H16Cl2N4O3 [M]+419.26, found 419.2.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3OC)oc2C)c1)C(=O)O
Yield: 56 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 56% yield as a pale yellow solid. MS: (M+H)+ 435.3.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([OH:19])([CH3:18])[C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:22]([C@:24]1([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]1=[O:30])#[CH:23]>>[OH:19][C:8]1([CH3:18])[C:9]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:23]#[C:22][C@:24]3([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[CH:21]=[CH:20][C:5]=2[O:6][CH2:7]1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(Br)cc1-2
Product: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4-hydroxy-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (0.11 g) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford methyl 4-hydroxy-9-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4-methyl-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate which was directly subjected to conditions described in General Procedure M to afford 5 mg and 5.6 mg (9% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined. M+1=414.0.
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Br>C(Cl)Cl>[CH3:1][N:2]([O:24][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COCCOCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCON(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (600 mg, 1.65 mmol) in methylene chloride (4 ml) containing diisopropylethylamine (0.43 ml, 1.5 eq.) is added (2-methoxy)ethoxymethyl bromide (310 mg, 1.5 eq.) The mixture is stirred at RT for 16 hours. The reaction mixture is then taken up in methylene chloride, washed, dried, evaporated and purified by prep. TLC to yield N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl](2-methoxy)ethoxymethoxyamine (IXA, R is CH3OCH2CH2OCH2).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 39 %

Procedure:
A mixture of (R)-tert-butyl-dimethyl-(3-oxiranyl-propoxy)-silane (13 g, 60 mmol; prepared according to Org. Lett. (2005), 7, 3997) and 6-amino-4H-benzo[1,4]oxazin-3-one (9.9 g) in EtOH/H2O (9:1, 325 mL) was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue purified by CC (Hept/EA 1:1) to give the desired intermediate as a brown oil (8.9 g, 39% yield).
Reaction SMILES: [F:1][CH:2]([F:22])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[F:21])[NH:8][C:7](=O)[CH2:6][CH2:5][C:4]1([F:11])[F:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[F:1][CH:2]([F:22])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[F:21])[NH:8][C:7](=[S:32])[CH2:6][CH2:5][C:4]1([F:11])[F:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCC(F)(F)[C@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)N1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c([C@@]2(C(F)F)NC(=S)CCC2(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 172.9 %

Procedure:
To a solution of (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidin-2-one (1.00 g, 3.08 mmol) in toluene (5 mL) was added Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithia-diphosphetane-2,4-disulfide) (686 mg, 1.70 mmol). The mixture was stirred at 100° C. for 2 hours. TLC analysis showed no starting material remained. The mixture was concentrated and the crude product was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=5:1) to give (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidine-2-thione (1.00 g, 2.94 mmol, 95.4% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+]>>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Yield: 97.4 %

Procedure:
Reaction of 2-chloronitrobenzene (10 g, 63 mmole), benzylamine (40 g, 380 mmole) and ammonium acetate (4.6 g) substantially as described in 1C above produced 14 g (98%) of title compound as orange crystals: mp 65°-67°.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:14]([NH2:18])[CH2:15][CH:16]=[CH2:17]>>[CH2:14]([NH:18][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCCCCCCCC(=O)O
Reactant: C=CCCN
Product: C=CCCCCCCCCC(=O)NCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from undec-10-enoic acid and but-3-en-1-amine. The resulting yellow solid was purified by silica gel chromatography (5:1 hexanes:ethyl acetate) to afford the desired product as a white solid. IR (neat): 3296 (br, s), 3078 (m), 2925 (s), 2854 (s), 1640 (s), 1548 (s), 1437 (s), 1359 (m), 1271 (m), 1151 (m), 991 (s), 909 (s), 722 (m), 634 (m); 1H NMR (400 MHz, CDCl3): δ 5.85-5.71 (2H, m), 5.45 (1H, s, br), 5.12-4.91 (4H, m), 3.33 (2H, dt, J=6.8, 6.4 Hz), 2.25 (2H, ddd, J=13.6, 6.8, 0.8 Hz), 2.14 (2H, t, J=7.6 Hz), 2.06-2.00 (2H, m), 1.65-1.57 (2H, m), 1.38-1.24 (10H, m); 13C NMR (100 MHz, CDCl3): δ 173.2, 139.3, 135.5, 117.3, 114.3, 38.4, 37.0, 34.0, 33.9, 29.5, 29.4, 29.4, 29.2, 29.0, 25.9; HRMS (ESI+) [M+H]+ calcd for C15H28N1O1: 238.2171. found: 238.2167. For proof of stereochemistry, see FIG. 3.
Reaction SMILES: [CH3:1][C:2]12[CH2:27][CH:6]([N:7]([C:9]([C:11]3[CH:26]=[CH:25][C:14]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:29])([CH3:28])[CH2:3]2.S(Cl)(Cl)=O.C[N:35](C=O)C>C(Cl)Cl>[CH3:1][C:2]12[CH2:27][CH:6]([N:7]([C:9]([C:11]3[CH:26]=[CH:25][C:14]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([C:22]([NH2:35])=[O:23])[CH2:18][CH2:17]4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:29])([CH3:28])[CH2:3]2
Reactant: CN(C)C=O
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(OC3CCC(C(=O)O)CC3)cc2)C1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(OC3CCC(C(N)=O)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 4-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexanecarboxylic acid (4 g, 10.01 mmol) in DCM (75 mL) was added thionylchloride (1.5 mL) and dry DMF (0.5 mL). The resulting mixture was stirred for 16 hrs at room temperature and the volatiles evaporated in vacuo. The residue was dissolved in DCM (50 mL), added dropwise to an ice cooled solution of conc. aqueous ammoniac (150 mL) and TEA (7 mL) and stirred for 1 hr. The phases were separated and the organic phase dried (Na2SO4), filtered and evaporated which afforded 3.5 g (88%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[C:5]([F:8])=[N:6][CH:7]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH2:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(F)c(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(N)cnc1F
Temperature: 100 °C
Yield: 98 %

Procedure:
To a stirred solution of 5-amino-2-fluoro-3-bromopyridine from step 126b above (3.25 g, 17.0 mmol) in toluene (20 mL) was added tributyl(vinyl)tin (Aldrich, 7.64 g, 20.4 mmol) followed by tetrakis(triphenylphosphine)palladium (Aldrich, 0.63 g, 1.7 mmol). The reaction mixture was heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the desired material as beige solids (2.30 g, 98%): 1H NMR (CDCl3, 300 MHz) δ3.61 (br s, 2H), 5.44 (d, J=11.5 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 6.66 (m, 1H), 7.18 (dd, J=3.0 Hz, 5.0 Hz, 1H), 7.52 (m, 1H); MS (CI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC.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>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
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: O
Product: FC(F)(F)c1cc(-c2cc3ccccc3o2)c2cccc(C(F)(F)F)c2n1
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
A solution of 4-bromo-2,8-bis(trifluoromethyl)quinoline (500 mg, 1.45 mmol) in dry dimethoxyethane (10 mL) was treated with tetrakis(triphenylphosphine)palladium (2.3 mg, 10 mol %), stirred for 10 min, treated with benzofuran-2-boronic acid (235 mg, 1.45 mmol) and 2-M Na2CO3 solution (1.45 mL, 2.9 mmol) then refluxed for 2 h. The mixture was cooled, treated with water (10 mL), extracted with EtOAc (3×20 mL), the organic phase was washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and the resulting yellow solid recrystallised from heptane to give the title compound (351 mg, 64%) as an off-white crystalline solid: mp 129-130° C.; IR νmax (Nujol)/cm−1 2924, 1592, 1463, 1314, 1145, 1116, 1010, 749 and 691; NMR δH (400 MHz, CDCl3) 7.35 (1H, t, J 7.1 Hz), 7.42-7.47 (2H, m), 7.65 (1H, d, J 7.5 Hz), 7.73 (1H, d, J 8.0 Hz), 7.80 (1H, t, J 7.9 Hz), 8.19-8.23 (2H, m) and 8.86 (1H, d, J 9.0 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7].Cl[CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1>CN(C=O)C>[F:13][C:8]1[C:5]([CH:6]=[O:7])=[C:4]([OH:3])[CH:11]=[C:10]([O:12][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH:9]=1
Reactant: O=Cc1c(O)cc(O)cc1F
Reactant: ClCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(O)cc(OCc2ccsc2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
Sodium hydride (0.52 g, 60% dispersion in mineral oil) is added portionwise over 30 minutes to a solution of 2,4-dihydroxy-6-fluorobenzaldehyde (2 g) in DMF (50 mL) at 0° C. The mixture is stirred at 0° C. for 30 minutes then a solution of 3-chloromethylthiophene (1.72 g) in DMF (50 mL) is added and the mixtured stirred at 60° C. for 16 hours. The reaction is concentrated in vacuo and the residue partitioned between diethyl ether (50 mL) and water (50 mL). The aqueous phase is extracted four times with diethyl ether (50 mL) and the combined organic phases washed with brine (50 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:4 v/v). Fractions homogeneous in the required product are combined and evaporated to give a pale yellow solid which is triturated with diisopropyl ether to give 6-fluoro-2-hydroxy-4-(3-thienylmethoxy)benzaldehyde (1.1 g) as a yellow solid.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH2:5]([C@@H:7]1[O:9][CH2:8]1)[Cl:6]>C(OCC)C>[CH2:1]([O:4][CH2:8][C@@H:7]([OH:9])[CH2:5][Cl:6])[CH:2]=[CH2:3]
Reactant: ClC[C@H]1CO1
Reactant: C=CCO
Solvent: CCOCC
Product: C=CCOC[C@@H](O)CCl
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A boron trifluoride-diethyl ether complex (0.34 ml) was added to allyl alcohol (11 ml), and the mixture was warmed to 45° C. Then, (R)-epichlorohydrin (5.0 g) was added and the mixture was stirred at the same temperature for 1.5 hours. Diethyl ether was added, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the crude title compound (10 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:38]([O:40][CH3:41])=[O:39])#N>C1COCC1>[CH2:9]([N:16]1[C:22](=[O:23])[CH:21]([C:38]([O:40][CH3:41])=[O:39])[CH2:20][O:19][CH2:18][CH:17]1[CH3:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C#N
Reactant: CC1COCCC(=O)N1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1COCC(C)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of lithium diisopropylamide in THF (0.101 M, 100 mL, 10.1 mmol, 1.30 equiv) freshly prepared at −78° C. was added via cannula to a solution of 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3, 1.71 g, 7.80 mmol, 1 equiv) in THF (100 mL) at −78° C. and the resulting mixture was stirred for 20 min. HMPA (1.36 mL, 7.80 mmol, 1.00 equiv) was added followed by methyl cyanoformate (1.24 mL, 15.6 mmol, 2.00 equiv). The resulting mixture was warmed to 0° C., stirred for 20 min, and then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4) as a mixture of diastereomers (colorless oil). LRMS m/z (M+H) 278.2 found, 278.1 required.
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6][CH:5]=[CH2:4]
Reactant: O=CO
Reactant: CCCCCCC
Product: C=CC=CCCCCCCCCCC=O
Yield: 94 %

Procedure:
The Grignard solution is then added to a mixture of 1,4-pentadien-3-yl isobutyrate ester (114 g, 0.740 mol) and LiCuBr2 reagent (1 M/THF, 86 mL) at a rate that maintains the reaction temperature between 25-30° C., with cooling as necessary. The mixture is stirred for 15 minutes then quenched with aqueous citric acid solution (1 L). The layers are separated and the organic portion is washed with water (2×) and dilute sodium hydroxide solution (until pH basic). The crude organic portion is then stripped of solvent and distilled to afford 56.2 g of the 11,13-tetradecadienal DEA product (b.p. 150° C., 0.1 mm Hg, Yld. 27%, m/z 282), which is subsequently deprotected at room temperature with formic acid in heptane to give 11,13-tetradecadienal (40.0 g, Yld. 94%, E/Z 76:24).