Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H:32](CCN1CC(OC2C=CC(Cl)=C(C)C=2)C1)CO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:28][C:29]=1[CH3:32]
Reactant: Cc1cc(OC2CN(CC[C@H](N)CO)C2)ccc1Cl
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)c(C)c3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[C:5]([C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[C:6]#[N:7])[CH3:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([Cl:34])[C:25]=1[NH:35][NH2:36].Cl>C(O)C>[NH2:7][C:6]1[N:35]([C:25]2[C:24]([Cl:23])=[CH:29][C:28]([C:30]([F:31])([F:33])[F:32])=[CH:27][C:26]=2[Cl:34])[N:36]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1
Reactant: CCOC(OCC)=C(C#N)C(=O)c1cccc(C(F)(F)F)c1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
An aliquot of the above solution of step A containing approximately two millimoles of 3,3-bis-ethoxy-2-(3-trifluoromethylbenzoyl)acrylonitrile was reacted with 0.49 g (2.0 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol under reflux overnight. The cooled mixture was poured into dilute hydrogen chloride (HCl) and the product was extracted into ethyl acetate (EtOAc), washed with water and brine, and dried over magnesium sulfate (MgSO4). Chromatography on silica gel with 4:1 hexane/EtOAc gave the title product, 320 mg (31%), m.p. 77-78° C. from pentane.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2(O)[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[Na+].[Na+].S(=O)(=O)(O)O.O>C(OCC)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9](=[O:19])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC1(C)C=CC(O)(Cc2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)=CC1=O
Reaction time: 0.67 h
Yield: 189.6 %

Procedure:
A solution of the 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-2-en-1-ol (368 g, 1.47 mol) obtained in (a) in 40/60 petroleum (40 ml) was added in a steady stream to a solution of sodium dichromate (217 g, 0.74 mol) in dilute sulphuric acid (250 g, 2.6 mol 98% sulphuric acid in 1.5 liters of water). The reaction mixture was then held at a temperature between 10° and 30° C. and stirred for 40 minutes. Water (500 ml) and diethyl ether (700 ml) were added and the aqueous layer extracted twice with diethyl ether (2×700 ml). The organic phases were then combined and backwashed with saturated sodium bicarbonate solution (1×500 ml) and water (1×500 ml). The solvent was then flashed off to give 349 g crude 1-(4-chlorobenzyl)-4,4-dimethylcyclohex -1-en-3-one as a beige coloured granular solid. Trituration in petrol gave a pure sample of the desired product, m.pt. 87°-90° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:34])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:32][CH:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:16]([F:15])([F:33])[F:34])=[N:18][N:19]=4)[N:22]=3)[CH2:27][CH2:28]2)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1nnc2ccc(N3CCC(Oc4ccc(OCc5ccccc5)cc4)CC3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
DIAD (2.262 mL, 11.49 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (3 g, 10.44 mmol), 4-(benzyloxy)phenol (2.300 g, 11.49 mmol) and triphenylphosphine (3.01 g, 11.49 mmol) in THF (50 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 4 hours. The crude oil was triturated with MeOH to give a solid which was collected by filtration and dried under vacuum to give 6-[4-[4-(benzyloxy)phenoxy]piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.53 g, 52%) as a solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([NH2:13])=[O:12].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[C:11]([CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:15]([Cl:14])(=[O:17])=[O:16])[CH:6]=2)[O:1]1)(=[O:12])[NH2:13]
Reactant: O=S(=O)(O)Cl
Reactant: NC(=O)C1CCc2ccccc2O1
Product: NC(=O)C1CCc2cc(S(=O)(=O)Cl)ccc2O1
Temperature: 0 °C
Yield: 73 %

Procedure:
The compound from Example 21 (2.0 g, 11.3 mmol) was added in portions over 10 minutes to cooled (0° C.) chlorosulfonic acid (9 mL). After 75 minutes the mixture was added slowly and dropwise to ice (150 g). The mixture was filtered and the solids washed with water (3×20 mL) and dried at 50° C. in vacuo to give a colorless powder (2.29 g, 73%). Mp 147-148° C.; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.50 (br s, 1H), 5.77 (br s, 1H), 4.68 (dd, J=9.4 Hz, 3.1 Hz, 1H), 2.95 (m, 2H), 2.52 (m, 1H), 2.16 (m, 1H).
Reaction SMILES: C(OC(N1CCC(C(O[C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[CH2:44]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([CH:60]([O:65]S(C(F)(F)F)(=O)=O)[C:61]([F:64])([F:63])[F:62])[CH2:56][CH2:55]1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:44]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([CH:60]([O:65][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[C:61]([F:64])([F:63])[F:62])[CH2:56][CH2:55]1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(OCc1ccccc1)N1CCC(C(OS(=O)(=O)C(F)(F)F)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C4CCN(C(=O)OCc5ccccc5)CC4)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (300 mg, 0.92 mmol), 4-(2,2,2-trifluoro-1-trifluoromethanesulfonyloxyethyl)piperidine-1-carboxylic acid benzyl ester (870 mg, 2.1 mmol) and Cs2CO3 (680 mg, 2.1 mmol) were suspended in DMF (5 mL), stirred at RT for 2 h and then heated at 80° C. for 18 h. The reaction mixture was then quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) affording the title compound (210 mg, 37%). LCMS: RT 4.04 min [M+H]+ 625.0.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:13]CC(C1C=C(CC)C=CN=1)=O>>[Br:13][CH2:2][C:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C(C)C)ccn1
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: CC(C)c1ccnc(C(=O)CBr)c1

Procedure:
* 2-Bromoacetyl-4-isopropylpyridine was prepared from 2-acetyl-4-isopropylpyridine (K. Ishihama et al., J. Agric. Food Chem., 1992, 40, 1647) according to the procedure for preparing 2-bromoacetyl-4-ethylpyridine described in Example 57.
Reaction SMILES: [C:1]([CH:4]([CH:6]([C:8]([OH:10])=[O:9])O)O)([OH:3])=[O:2].[CH2:11]([N:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)[CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([SiH](CC)CC)C>C(O)(=O)C>[C:8]([OH:10])(=[O:9])/[CH:6]=[CH:4]/[C:1]([OH:3])=[O:2].[CH2:11]([N:18]([CH:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)[CH3:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(Cc1ccccc1)C1CCN(c2ccc(CO)cc2)CC1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC[SiH](CC)CC
Solvent: CC(=O)O
Product: Cc1ccc(N2CCC(N(C)Cc3ccccc3)CC2)cc1
Product: O=C(O)/C=C/C(=O)O

Procedure:
1.9 g (6.1 mmol) of the base of the product from Example 23 were reduced with 1.1 g (9.2 mmol) of triethylsilane and 8.0 g of glacial acetic acid in a similar manner to Example 14. 2.0 g of 4-(N-benzyl-N-methylamino)-1-(4-tolyl)piperidine fumarate were obtained. Melting point 161°-163° C.
Reaction SMILES: C(O[C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])CCC.[Cl:19][C:20]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[Cl:19][C:20]1[CH:27]=[C:26]([CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:13])([CH3:14])[CH3:15])[C:28]#[N:29]
Reactant: CCCCOc1c(NC(C)C(C)(C)C)c(=O)c1=O
Reactant: N#Cc1ccc(CN)c(Cl)c1
Solvent: C1CCOC1
Product: CC(Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O)C(C)(C)C
Reaction time: 62 h
Yield: 44.6 %

Procedure:
A solution of 3-butoxy-4-(1,2,2-trimethyl-propylamino)cyclobut-3-ene-1,2-dione (1.27 g, 5.0 mmol, Example 5), 2-chloro-4-cyanobenzylamine (0.833 g, 5.0 mmol, Example 2, Step 3) and tetrahydrofuran (8 mL) was stirred at room temperature for 23 hours, refluxed for 4 hours and allowed to stand at room temperature for approximately 62 hours. The mixture was freed of solvent and the residue was triturated with diethyl ether and dried. The resulting white solid (1.096 g) was recrystallized three times from methanol to yield 771 mg (45%) of the title compound as a faintly pink solid: mp 250.0°-251.5° C. (softens 248.0° C.); 1H NMR (DMSO-d6) δ8.10 (d, 1H), 7.88 (m, 1H), 7.70 (br m, 1H), 7.61 (d, 1H), 7.37 (br m, 1H), 4.88 (m, 1H), 3.91 (br m, 1H), 1.11 (d, 3H), 0.86 (s, 9H) ppm IR (KBr): 3200, 2230, 1790, 1635 cm-1 ; MS (m/z) 345/347 (M+). HPLC indicates a major component (98.7%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[C:25]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1)(=[O:26])[CH:24]=[CH2:23].[ClH:22]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)COC21CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC2(CC1)OCc1ccccc12
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of spiro[isobenzofuran-1(3H),4'-piperidine] (1.9 g) in dichloromethane (40 ml) was added triethylamine (2.3 ml). After cooling to 10° C. a solution of 3-chloropropionic acid chloride (1.7 g) in dichloromethane (15 ml) was added dropwise during 10 min. The mixture was stirred at room temperature for another hour. The 1'-(3-chloropropanoyl)-spiro[isobenzofuran-1(3H),4'-piperidine] was purified by subjecting the reaction mixture to column chromatography on silica gel (eluted with ethyl acetate/heptane 60:40). Yield 1.8 g as an oil. As a result of elimination of hydrogen chloride 1'-(2-propenoyl)-spiro[isobenzofuran-1(3H),4'-piperidine] was isolated as a by-product. Yield 0.7 g as an oil. Both the 3-chloropropanoic acid amide and the propenoic acid amide were dissolved in methyl isobutyl ketone (MIBK) (40 ml). To this solution K2CO3 (1.5 g) and spiro[isobenzofuran-1(3H),4'-piperidine] (1.8 g) were added. The resulting mixture was refluxed overnight. Inorganic salts were subsequently filtered off and MIBK evaporated in vacuo. The resulting 1,3-bis[spiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl]propanoic acid amide was purified by column chromatography on silica gel (eluted with ethyl acetate containing 4% of triethylamine). Yield 2.2 g as a viscous oil. To a suspension of LiAlH4 (0.8 g) in dry THF was added all of the above isolated mono-amide (2.2 g) in THF solution (25 ml). The resulting mixture was refluxed for 2 hours. Excess LiAlH4 was destroyed by cautiously adding concentrated aqueous NaOH (1 ml) at 10° C. followed by addition of water (5 ml). Inorganic salts were filtered off and THF was evaporated in vacuo. The remaining oil was dissolved in ethanol (15 ml) and fumaric acid was added (1.1 g). Upon heating to 60° C. the fumaric acid salt of the title compound 2a crystallized. Yield 2.2 g. Mp 232°-233 ° C. 1H NMR (DMSO-d6) δ1.70 (d,4H), 1.95 (broad p,2H), 2.10 (dt,4H), 2.65 (t,4H), 2.70-2.80 (m,4H), 3.15 (broad d,4H), 5.00 (s, 4H), 6.55 (s,4H), 7.20-7.35 (m,8H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:17]([N:20]1[C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[N:23][NH:22][C:21]1=[S:31])[CH:18]=[CH2:19].[CH2:32]=O>C(O)(C)(C)C>[CH2:17]([N:20]1[C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[N:23][N:22]([CH2:32][N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]2)[C:21]1=[S:31])[CH:18]=[CH2:19]
Reactant: C=O
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: C=CCn1c(-c2cccnc2)n[nH]c1=S
Solvent: CC(C)(C)O
Product: C=CCn1c(-c2cccnc2)nn(CN2CCN(c3cccc4c3OCCO4)CC2)c1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(1,4-benzodioxan-5-yl)piperazine (1 g; prepared in a similar manner to that described in Example 2), 4-allyl-5-(3-pyridyl)-1,2,4-triazole-3(2H,4H)-thione (1 g), 37-40% aqueous formaldehyde solution (0.5 ml) and t-butanol (60 ml) was stirred at ambient temperature for 30 minutes, heated under reflux for 15 minutes, then the solvent was removed in vacuo. The residue was triturated with a 1:1 mixture of cyclohexane and ether (40 ml), and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 4-allyl-2-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-5-(3-pyridyl)-1,2,4-triazole-3(2H,4H)-thione as a white solid (0.62 g), m.p. 122-127° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=CCc2nccn2Cc2ccccc2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C=CCc2nccn2Cc2ccccc2)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (3 g; 7 mmol), sodium hydroxide (0.8 g; 20 mmol) and distilled water (5 ml) in methanol (50 ml) was refluxed for 4 hours. After evaporation to dryness and acidification to pH 6 with 6N HCl, the resulting solid was triturated with water and ether to give 4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid as a mixture of E and Z isomers.
Reaction SMILES: ClCCl.[CH3:4][O:5][CH:6]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][OH:8].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([O:8][CH2:7][CH:6]([O:5][CH3:4])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:32])=[O:31]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OC
Yield: 99.9 %

Procedure:
To 120 ml of dichloromethane are added 12.0 g of 2-methoxy-3-octadecyloxypropanol and 6.07 ml of triethylamine, to which 4.98 g of methanesulfonyl chloride is added dropwise with stirring under ice cooling. Thereafter, the mixture is stirred at room temperature for 2 hours to complete the reaction. The reaction mixture is then washed with water, an aqueous sodium bicarbonate solution and again water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to leave 14.6 g (100%) of the captioned compound.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:12]([CH:22]([CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[O:24])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>C1COCC1>[CH2:12]([CH:22]([CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]([OH:24])[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC/C=C\CCCC(C=O)CCC/C=C\CCCCC
Reactant: CCCCC/C=C\CCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(O)CC/C=C\CCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A 100 mL round bottom flask was charged with magnesium turnings (0.6 g, 25.7 mmol) and a stir bar. The flask was dried with a heat gun for 5 minutes. The flask was charged with THF (5 mL) and a single grain on iodine. A solution of (Z)-1-bromonon-3-ene (4.5 g, 22.0 mmol) in THF (5 mL) was added slowly to the mixture and reaction was refluxed for 30 minutes under nitrogen. The solution was cooled to room temperature and a solution of (Z)-2-((Z)-dec-4-enyl)dodec-6-enal 7 (4.7 g, 14.7 mmol) in THF (5 mL) was added. The solution was stirred overnight at room temperature and upon completion the mixture was poured into 5% HCl (50 mL) and ice (100 mL). The solution was extracted with ether (2×150 mL) and the combined ether extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (column: 2″ W×8″ L; eluted with 100% Hexanes to 5% ethyl acetate in hexanes) to afford (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-ol 17 as a colorless oil (5.4 g, 82%). Rf 0.5 (10% EtOAc-Hexanes).
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[C:102]([O:110][CH3:111])=[N:103][N:104]([CH2:106][CH2:107][CH2:108][OH:109])[CH:105]=2)=[CH:99][CH:100]=1>>[OH:109][CH2:108][CH2:107][CH2:106][N:104]1[CH:105]=[C:101]([C:98]2[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:100][CH:99]=2)[C:102]([O:110][CH3:111])=[N:103]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cn(CCCO)nc2OC)ccc1N
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4OC)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 35 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 251 mg, 0.553 mmol) and 3-amino-6-[1-(3-hydroxypropyl)-3-methoxy-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 48C, 177 mg, 0.580 mmol) to afford 139 mg of the title compound (35%). 1H NMR (400 MHz, CD3OD) δ 8.90 (br. s., 1H), 8.33 (s, 2H), 7.85 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.02-7.07 (m, 1H), 6.90 (td, J=2.4, 8.1 Hz, 1H), 4.15 (t, J=6.7 Hz, 2H), 4.00-4.10 (m, 7H), 3.90 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 3.26 (s, 2H), 2.98 (s, 3H), 2.08 (quin, J=6.5 Hz, 2H), 1.20-1.27 (m, 6H). MS (ESI): m/z=723.42 [M+H]+. UPLC: tR=1.31 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH3:20]
Reactant: Nc1cc2ccccc2cc1N
Reactant: CCOC(=O)CCBr
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1cc2ccccc2cc1N

Procedure:
A solution of 2,3-diaminonaphthalene (14.3 g, 90.4 mmol) and ethyl 3-bromopropionate (14 mL, 0.108 mol) in DMF (150 mL) was heated to 50° C. for 24 h. The reaction mixture was poured into water (600 mL) and the product was extracted into CH2Cl2 (2×200 mL). The combined organics were washed three times with water and dried over Na2SO4. The solvent was evaporated in vacuo and the resultant residue was purified by flash chromatography using 27% to 40% EtOAc in hexane as the eluant to give the product as a brown solid, 7.6 g (33%): MS m/z 259 (MH+); 1H NMR (DMSO-d6) δ 1.22 (t, 3H), 2.73 (t, 2H), 3.37-3.45 (m, 2H), 4.12 (q, 2H), 5.03 (br s, 2H), 5.09 (br t, 1H), 6.71 (s, 1H), 6.85 (s, 1H), 6.98-7.05 (m, 2H), 7.36-7.43 (m, 1H) and 7.47-7.53 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:43]=[CH:42][C:41](CO)=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:41]2[CH:42]=[CH:43][C:38]([CH3:37])=[CH:39][CH:40]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: Cc1ccc(CO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccc(C)cc4)cc3C)c2cc1OC
Yield: 95.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (4-methylphenyl)methanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (139 mg, yield 88%).