Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Br)[CH:21]=1>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([OH:28])=[O:18])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)c1

Procedure:
3-(2′-Nitro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-hydroxy-2′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd. Morcambe, Lancashire, UK). Yield: 82 mg. Mass spectrum (ES) MH+=350.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][C:13]=2[O:21][CH3:22])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].[CH:29]([CH:31]=[CH2:32])=[O:30]>O1CCOCC1>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][CH3:20])[CH:16]=[CH:17][C:12]=1[O:11][CH2:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:31]([CH:29]=[O:30])[CH2:32][O:1]2)=[CH:6][CH:7]=1
Reactant: CCCc1ccc(OCc2ccc(C=O)c(O)c2)c(OC)c1
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCc1ccc(OCc2ccc3c(c2)OCC(C=O)=C3)c(OC)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2-hydroxy-4-[(2-methoxy-4-propylphenoxy)methyl]benzaldehyde (120 mg) in dioxane (2.4 mL) were added K2CO3 (55.2 mg) and acrolein (0.267 mL) at 25° C. The reaction mixture was warmed to 100° C., followed by stirring at 100° C. for 15 hours. The reaction mixture was left to be cooled to 25° C., and then filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 7-[(2-methoxy-4-propylphenoxy)methyl]-2H-chromene-3-carbaldehyde (104.2 mg) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:21]([F:23])([F:22])[F:24])=[CH:11][C:12]=2[S:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:25])=[CH:6][CH:7]=1
Reactant: OO
Reactant: FC(F)(F)c1cc(Sc2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=S(c1ccc(Cl)cc1)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Yield: 65.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(p-chlorophenyl)thio]-5-(trifluoromethyl)pyrrole (2.57 g, 6.6 mmol) and 30% hydrogen peroxide solution (0.83 g, 7.3 mmol) in acetic acid is stirred at room temperature overnight and poured into water. The resultant aqueous mixture is filtered to obtain a solid. A solution of the solid in methylene chloride is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:3 ethyl acetate/hexanes solution gives the title product as a white solid (1.75 g, mp 174°-176° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[N:29][CH:30]=1>>[ClH:31].[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[N:29][CH:30]=3)=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cn1ccc2cc(N)ccc21
Product: Cl
Product: Cn1ccc2cc(NC(=O)Nc3ccc(Cl)nc3)ccc21
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 5-amino-1-methyl-1H-indole (D3), carbonyl diimidazole and 5-amino-2-chloropyridine, using a procedure similar to that described in Example 13. m.p. 212° C.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1>[Pd].C(O)C>[CH3:13][C:12]1[C:7]([CH3:6])=[CH:8][C:9]([NH2:16])=[C:10]([O:14][CH3:15])[CH:11]=1
Reactant: COc1cc(C)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)c(C)cc1N
Reaction time: 5 h
Yield: 82 %

Procedure:
Tetrahydrofuran(100 ml) and ethanol(40 ml) were added into 4,5-dimethyl-2-nitroanisole(7.80 g, 0.043 mol) and then added 10% Pd/activated carbon(0.57 g) slowly, hydrogenated for 5 hrs. The reaction was completed by the same way with the above and the resulting product was purified by column chromatography to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C(Cl)Cl.CO>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]([NH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1)=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
3-Aminopyrazole (9 g, 108 mmol) was dissolved in DCM (250 ml). Triethylamine (27 g, 262 mmol) was added in one portion. Pivaloyl chloride (30 g, 248 mmol) was added slowly at room temperature. After stirring at room temperature for 6 hours, the solvent was concentrated under reduced pressure to give a solid. The solid was dissolved in methanol (200 ml). Aqueous NaOH (2.5M, 120 ml) was added slowly and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure. The slurry was transferred into water (300 ml). The solid was filtrated and dried to give the title product (13.5 g) as a yellow solid, yield: 76%. 1H-NMR (400 MHz, d6-DMSO): δ 12.3 (s, 1H), 9.77 (s, 1H), 7.58 (s, 1H), 6.49 (s, 1H), 1.2 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:31]([N:33]1[CH2:37][CH2:36][C@H:35]([F:38])[CH2:34]1)=[O:32])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([O-:44])=[O:43].[F:38][C@H:35]1[CH2:36][CH2:37][N:33]([C:31](=[O:32])[C@@H:8]([NH3+:7])[C@H:9]([CH:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:30])[C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)[CH3:10])[CH2:34]1
Reactant: C[C@@H](C1CCC(NC(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C1CCC(NC(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H]([NH3+])C(=O)N1CC[C@H](F)C1
Product: O=C([O-])C(F)(F)F

Procedure:
To a solution of the material prepared in Step A (0.017 g, 0.036 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 3 h at ambient temperature the reaction was concentrated in vacuo, affording the title compound as a white solid. LC/MS 406.3 (M+1).
Reaction SMILES: CSC.[CH3:4][C:5]([CH3:21])([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]([O:18][CH2:19][CH3:20])[CH:12]=1)[C:6](OCC)=[O:7].CC(O)C>C(OCC)C>[CH2:19]([O:18][C:13]1[CH:12]=[C:11]([C:5]([CH3:21])([CH3:4])[CH2:6][OH:7])[CH:16]=[CH:15][C:14]=1[I:17])[CH3:20]
Reactant: CCOC(=O)C(C)(C)c1ccc(I)c(OCC)c1
Solvent: CCOCC
Solvent: CSC
Solvent: CC(C)O
Product: CCOc1cc(C(C)(C)CO)ccc1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.3 %

Procedure:
Boran dimethylsulfide (33 mL, 66 mmol, 2M in tetrahydrofuran) was added to a solution of ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate (4.83 g, 13.3 mmol) in ethyl ether (40 mL). The reaction was stirred at room temperature for 3 d and stirred for an additional hour with 2-propanol (10 mL) to quench the excess borane. The solution was partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene (4.23 g, 99%) as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:24])=[C:21]([F:23])[F:22].C1(O)C=CC=CC=1>O.CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1F
Reactant: FC(F)=C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 0.33 h
Yield: 98 %

Procedure:
0.93 Gram of 4-acetylamino-3-fluorophenol, 0.15 g of potassium carbonate and 15 ml of dimethylformamide were added to a reactor and stirred for 20 minutes at an oil bath temperature of from 60° to 70° C. Thereafter, this solution was violently stirred at the same temperature for 1 hour under the stream of a tetrafluoroethylene gas in excess of said phenol. The reaction solution was cooled and after adding water, extracted with two 100-ml portions of diethyl ether. The ether layers were combined, washed with water, dried and concentrated to obtain a crude product. This crude product was subjected to chromatography on silica gel to obtain 1.46 g of 4-acetylamino-3-fluoro-1-(1,1,2,2-tetrafluoroethoxy)benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14](Cl)(Cl)=[S:15].O1CCOCC1>O>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([N:1]=[C:14]=[S:15])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1-c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: S=C=Nc1ccccc1-c1ccccc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of 2-aminobiphenyl (10.2 g), thiophosgene (10.4 g), dioxane (50 ml) and water (100 ml) was prepared with cooling in an ice bath. The temperature was raised to 30° C. and stirred for 3 hours at 30° C. to yield 2-biphenylylisothiocyanate as a yellow oil.
Reaction SMILES: I[C:2]1[C:8](I)=[C:7]([OH:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]=1[OH:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(NC(C)C)(C)C.[CH3:39][Si:40]([C:43]#[CH:44])([CH3:42])[CH3:41]>[Pd].C1(C)C=CC=CC=1>[CH3:39][Si:40]([CH3:42])([CH3:41])[C:43]#[C:44][C:2]1[C:8]([Si:40]([CH3:42])([CH3:41])[CH3:39])=[C:7]([OH:10])[C:6]([CH3:11])=[C:5]([CH3:12])[C:3]=1[OH:4]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(C)c(O)c(I)c(I)c1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: Cc1c(C)c(O)c([Si](C)(C)C)c(C#C[Si](C)(C)C)c1O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a degassed solution of 2,3-diiodo 5,6-dimethylhydroquinone (1)(3.6 g, 9.23 mmol), Pd"(PhCN)2Cl2 (176.9 mg, 0.46 mmol), PPh3 (278.2 mg, 1.06 mmol), and Cul (297 mg, 1.56 mmol) in 110 mL to toluene under argon were added 2.5 mL (18.5 mmol) of diisopropylamine and 4.0 mL (28.6 mmol) of (trimethylsilyl)acetylene. After stirring at room temperature for a day the reaction mixture was opened to air, filtered and concentrated under vacuo. Flash column chromatography with 7% ethyl acetate in petroleum ether produced yellow compound (2) with 50.2% yield (1.53 g). Melting point 76°-77° C.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([OH:29])[C@H:21]1[O:26][C:24](=[O:25])[C:23]([OH:27])=[C:22]1[OH:28])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:30](Cl)(=[O:36])/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH3:35]>N1C=CC=CC=1.ClCCl>[C:1]([O:18][CH2:19][C@H:20]([OH:29])[C@H:21]1[O:26][C:24](=[O:25])[C:23]([O:27][C:30](=[O:36])/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH3:35])=[C:22]1[OH:28])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C/C=C/C=C/C(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C/C=C/C=C/C(=O)OC1=C(O)[C@@H]([C@@H](O)COC(=O)CCCCCCCCCCCCCCC)OC1=O
Reaction time: 2 h

Procedure:
50 g (120 mmol; 1 eq.) of 6-O-palmitoyl-L-ascorbic acid were dissolved in 400 ml of pyridine in a 1 l 4-necked flask. 23.40 g (130 mmol; 1.1 eq.) of sorboyl chloride, dissolved in 30 ml of dichloromethane, were slowly added dropwise at an internal temperature of -15° C. Care was taken here that the internal temperature did not exceed -10° C. The mixture was brought to room temperature and additionally stirred for 2 hours. The reaction solution was concentrated on a rotary evaporator and then codistilled with toluene. The residue was taken up in a little dichloromethane and extracted with 1 M HCl. The organic phase was concentrated somewhat and treated with an excess of n-hexane. A white precipitate was deposited, which was dried in an oil pump vacuum.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.S1C=CN=C1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:37][C:38]1[CH:45]=[C:44]([OH:46])[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]>CN(C)C=O.C(OC(=O)C)C>[Cl:37][C:38]1[CH:45]=[C:44]([O:46][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: FC(F)(F)c1ccc(-c2nc(COC3CCCCO3)c(CCl)s2)cc1
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cscn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
3.0 g 5-(Chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluormethyl)phenyl]-1,3-thiazole (synthesis is described in WO2002/067912) thiazole were dissolved in 100 ml dimethylformamide. 5.0 g of cesium carbonate and 1.53 g 2-Chloro-4-hydroxybenzonitrile were added and the mixture was stirred at room temperature overnight. Then 300 ml of ethylacetate were added, the mixture washed three times with saturated NaHCO3 solution and brine then dried over MgSO4. The solvent was removed in vacuo to obtain 4.1 g of crude 2-Chloro-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as yellow oil. This material was used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([N:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=2)[CH:58]=[N:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([N:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[C:63]([NH:67][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:64]=[CH:65][CH:66]=2)[CH:58]=[N:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 52.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-benzyl-1H-pyrazol-4-yl)-phenylamine (0.016 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 55% yield: LCMS (ESI) m/z 438 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([NH:16][C:17]2[CH:18]=[N:19][N:20]([CH3:40])[C:21]=2[N:22]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OCC3C=CC=CC=3)[CH2:24][CH2:23]2)=[O:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1CC=CCC=1>[Pd].C(O)C>[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:21]2[N:20]([CH3:40])[N:19]=[CH:18][C:17]=2[NH:16][C:14](=[O:15])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=2)[CH2:23][CH2:24]1
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(-c3ccccc3)n2)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3ccccc3)n2)c1N1CCC[C@@H](N)CC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
In a 40 mL sealed vial was added (R)-benzyl 1-(4-(5-fluoro-6-phenylpicolinamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate (62 mg, 0.11 mmol), 1,4-cyclohexadiene (0.11 mL, 1.14 mmol) and ethanol (7 mL). 10% Pd/C (18.2 mg, 0.017 mmol) was added and the reaction vial was vacuum purged with nitrogen three times. The reaction mixture was then stirred at 95° C. under nitrogen for 2 h. After cooling down to room temperature, the reaction mixture was filtered through Celite and rinsed thoroughly with methanol. The solvent was distilled off under reduced pressure to give the crude product which was purified via reverse phase HPLC to afford 229. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.18-7.98 (m, 4H), 7.68-7.48 (m, 3H), 3.68 (s, 3H), 3.25-3.03 (m, 5H), 2.02-1.75 (m, 3H), 1.74-1.51 (m, 3H). MS (ESI) m/z: 409.2 [M+H+].
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][C:7]([CH:14]=[CH:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:8][C:9]([O:11]CC)=[O:10]>O>[CH3:6][C:7]([CH:14]=[CH:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C=CCC(C)CCCC(C)C)=CC(=O)O
Yield: 58 %

Procedure:
To 350 ml. of ethanol, 105 ml. of water and 70 ml. of 50% aqueous sodium hydroxide is added 46.5 g. of ethyl 3,7,11-trimethyldodeca-2,4-dienoate (40% cis, trans and 60% trans, trans). The mixture is refluxed for about 19 hours. After cooling, ethanol is removed under reduced pressure and water added followed by extraction with ether to yield 3,7,11-trimethyldodeca-2,4-dienoic acid containing about 58% trans, trans isomer. Conversion of the thus-obtained acid to the S-benzyl-isothiouronium salt recrystallized from aqueous methanol, and regeneration of the acid with ether-aqueous hydrochloric acid provides crystalline trans, trans, 3,7,11-trimethyldodeca-2,4-dienoic acid.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6]O.[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[C:18]#[N:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C=O)c(OCc2ccccc2)c1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C#N)c(OCc2ccccc2)c1OC

Procedure:
A slurry of sodium acetate (17.06 g, 0.208 mol) and hydroxylamine (14.45 g, 0.208 mol) in glacial acetic acid (120 ml) was added to 2-benzyloxy-3,4-dimethoxybenzaldehyde (28.3 g, 0.104 mol) and the resulting suspension stirred at reflux for 18 hours. On cooling, water (250 ml) was added and the mixture extracted with dichloromethane (500 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with hexane:ethyl acetate (80:20 v/v) to give the subtitle compound as an oil that crystallised on standing (21.06 g, 75%). Rf 0.52 (ethyl acetate:hexane, 1:1, v/v). MS m/z 270 (MH)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[C:12]1(S(OC)(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH3:12][O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][Br:1])=[CH:5][CH:6]=1
Reactant: OCc1ccc(CCBr)cc1
Reactant: COS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCc1ccc(CCBr)cc1

Procedure:
The 1-(2-bromoethyl)-4-hydroxymethylbenzene (0.5 g) is then added to a solution of 0.44 g methyl benzenesulfonate and 0.32 g K2CO3 in 10 ml of methanol and allowed to react for 4 h. The solution is neutralized with methanolic HCl and extracted with ether. The ether extract is dried over Na2SO4, filtered, and the solvent removed under vacuum to yield 1-(methoxymethyl)-4-(2-bromoethyl)benzene (13).
Reaction SMILES: [C:1]([C:3]1([C:7]2(O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)#[N:2].O=P(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1([C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C2(C#N)CCC2)C1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(C2(C#N)CCC2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 116.3 %

Procedure:
To a solution of Example 265A (2.4 g, 9 mmol) in pyridine (50 mL) was added POCl3 (8.4 mL, 90 mmol) dropwise and the solution was stirred at 60° C. for 12 hours. Pyridine was removed under reduced pressure and the solution was basified with 1 N NaOH. The aqueous layer was extracted with EtOAc (25 mL×3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluted with petroleum ether:ethyl acetate=20:1 to obtain the title compound (2.6 g, 44.3% yield) as a colorless oil. 1H NMR: (400 MHz, CDCl3): δ 5.80 (d, J=9.6 Hz, 1H), 4.26-4.17 (m, 4H), 2.66-2.59 (m, 2H), 2.45-2.38 (m, 2H), 2.34-2.24 (m, 1H), 2.10-2.00 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(#N)C>>[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH2:13]3)[C:9]2=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1N(C2CCCCC2)CCC12CCCNC2
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1ccncc1)N1CCCC2(CCN(C3CCCCC3)C2=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride (15 mg, 0.000055 mol), isonicotinoyl chloride hydrochloride (12 mg, 0.000066 mol), and triethylamine (27 μL, 0.00019 mol) in acetonitrile (0.5 mL, 0.01 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC to afford 18 mg of the desired product. LC-MS: 342.3 (M+H)+.