Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.[CH:18]([C:20]1[O:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+].C(O)C>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].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:23]4[O:24][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=4)=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Clc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)o1
Yield: 38.2 %

Procedure:
300 mg of 2-(4-chlorophenyl)-6-iodoimidazo[1,2-a]pyridine, 118 mg of 5-formyl-2-furanboronic acid, 89 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium, 280 mg of potassium carbonate, 1.5 ml of ethanol and 1 ml of water are placed in a microwave tube and degassed with argon. The tube is placed in a microwave apparatus and irradiated at 90° C. for 30 min. After cooling, the catalyst is removed by filtration and washed with ethyl acetate. The organic phase is separated and dried and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 104 mg of compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:12][O:11][C:6]1[C:7]2[C:8](=[O:10])[O:9][C:16](=[O:18])[NH:1][C:2]=2[CH:3]=[CH:4][C:5]=1[O:13][CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)O)c1OC
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1OC
Temperature: 0 °C

Procedure:
10.0 g (50.7 mmol) 6-Amino-2,3-dimethoxy-benzoic acid were dissolved in 150 ml tetrahydrofuran, 6.52 g (22.0 mmol) triphosgene were added and the solution was refluxed for 3 h. After pouring on 400 ml of a ice/water mixture the precipitate was filtrated and rinsed with water and methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][NH:23][CH2:24]3)=[CH:19][CH:18]=2)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([CH3:30])[CH2:24]3)=[CH:19][CH:18]=2)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.42 mmol) 4-benzyloxy-1-[2-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 24.2) in 5.0 mL THF is added 68 μL (0.83 mmol) aqueous 37% formaldehyde solution. The mixture is acidified with 3 drops of acetic acid and then 97 mg (0.46 mmol) sodium triacetoxy-borohydride is added. The reaction mixture is stirred 2 h at RT and additional 68 μL (0.83 mmol) aqueous 37% formaldehyde solution and 97 mg (0.46 mmol) sodium triacetoxy-borohydride are added. The reaction mixture is stirred overnight and additional 68 μL (0.83 mmol) aqueous 37% formaldehyde solution and 97 mg (0.46 mmol) sodium triacetoxy-borohydride is added and the reaction mixture is stirred additional 48 h at RT. The mixture is poured into aqueous 10% Na2CO3-solution, the layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is washed a few times with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32]S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.7 g) was dissolved in 10 mL dry THF and 1320 mg triphenylphosphine and 691 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 minutes, then 992 μL DIAD was added dropwise. The reaction was stirred at room temperature for 3 hours and was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc). The resulting residue was dissolved in 20 mL dry DMF, then 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature. The reaction was stirred for 30 minutes and was partitioned between saturated aqueous NaHCO3 and diethyl ether. The aqueous layer was washed again with diethyl ether and the organic layers were combined. The organic layer was washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column)) to give 1.05 g of the product after drying. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.27-7.19 (m, 4H), 7.12 (m, 2H), 6.98 (m, 2H), 6.83 (d, 1H), 6.66 (d, 1H), 6.58 (m, 1H), 5.12-5.08 (m, 3H), 4.30 (m, 1H), 4.00 (m, 1H), 3.66 (s, 3H), 3.42 (m, 1H), 3.23 (m, 1H), 2.77 (m, 2H), 1.7-1.5 (m, 2H), 0.78 (t, 3H). LCMS: m/z 607.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([O:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:27][CH:26]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Cc1cccc(C)c1O
Agent: [Cu]I
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C

Procedure:
2,6-Dimethylphenol was added portionwise to a suspension of NaH (272 mg, 60% in oil, 6.8 mmol) in toluene (15 mL). After complete addition the mixture was heated under reflux for 15 min. and subsequently cooled to room temperature. To the resulting mixture was added a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (1.5 g, 4.5 mmol) in toluene (10 mL), followed by copper(I) iodide (438 mg, 2.3 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.48 mL, 2.3 mmol), and cesium carbonate (2.96 g, 9.1 mmol). The obtained mixture was heated under reflux for 3 days. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The layers were separated. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:heptanes 5:95) to afford 4-benzyl-2-[4-(2,6-dimethyl-phenoxy)-phenyl]-morpholine (1.2 g), which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:18]([F:21])([F:20])[C:17]1[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][N:24]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: FC(F)(F)c1cccnc1-c1ccc2c(Cl)ccnc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4ncccc4C(F)(F)F)ccc23)nc1

Procedure:
Heat a mixture of 5-chloro-2-(3-(trifluoromethyl)pyridin-2-yl)-[1,8]naphthyridine (62 mg, 0.2 mmol), 2-amino-5-trifluoromethylpyridine (32.4 mg, 0.2 mmol), xantphos (11.6 mg, 0.02 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol) and Cs2CO3 (130 mg, 0.4 mmol) in dioxane (2.0 mL) at 100° C. for 20 hours. Cool the mixture, concentrate under vacuum, dilute with EtOAc/water (5.0 mL each), filter through celite, wash celite with EtOAc (2×5 mL) and dry combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by preparative TLC using EtOAc as eluent to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) δ 10.15 (s, 1H), 9.1 (d, 1H, J=2.2 Hz), 9.0 (d, 1H, J=1.1 Hz), 8.95 (d, 1H, J=1.2 Hz), 8.68 (s, 1H), 8.50 (d, 1H, J=1.3 Hz), 8.43 (d, 1H, J=2.0 Hz), 8.12 (dd, 1H), 8.0(d, 1H, J=2.2 Hz), 7.81 (m, 1H), 7.49 (d, 1H, J=2.2 Hz). MS=436.08 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][C:9]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][C:9]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2ccccc2)CC2(NC(=O)NC2=O)c2cc(Br)ccc2O1
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CC2(NC(=S)NC2=O)c2cc(Br)ccc2O1
Yield: 61.8 %

Procedure:
A suspension of 6-bromo-2-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (1.16 g, 3 mmol) and Lawesson's Reagent (1.21 g, 3 mmol) in dry 1,4-dioxane (24 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column to give 6-bromo-2-methyl-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (748 mg, 61%). 1H-NMR (CDCl3): 1.75 (s, 3H), 3.78 (m, 2H), 5.79 (s, 1H), 6.94 (m, 1H), 7.14 (m, 1H), 7.22 (m, 1H), 7.26-7.53 (m, 5H), 8.39 (s, 1H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[C:45]3[CH:50]=[CH:49][C:48]([CH:51]4[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]4)=[CH:47][CH:46]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:51]1([C:48]2[CH:47]=[CH:46][C:45]([C:37]3[N:36]([C:33]4[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]5[CH:58]=[CH:59][C:19]([OH:18])=[CH:20][CH:21]=5)=[CH:31][CH:32]=4)[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=3)=[CH:50][CH:49]=2)[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1
Yield: 93.4 %

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-({4-[2-(4-cyclohexylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethyl}amino)-2-propanol (0.317 g, 0.396 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.21 g, 0.37 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:17]1([CH2:20][NH:21][C:22](=[O:38])[C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:7]1[C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([NH:21][CH2:20][CH:17]3[CH2:19][CH2:18]3)=[O:38])=[CH:24][CH:25]=2)=[CH:3][C:4]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(Cl)c(Br)c1)c1ccoc1
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1ccc(-c2cc(NC(=O)c3ccoc3)ccc2Cl)cc1
Temperature: 80 °C

Procedure:
N-(3-Bromo-4-chlorophenyl)-3-furamide (Intermediate 1, 63 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (60 mg), tetrakis(triphenylphosphine) palladium (5 mg) and aqueous sodium carbonate (2N, 0.5 ml) were mixed in DMF (1.2 ml) and heated at 80° C. under nitrogen for 18 hrs. The cooled reaction was absorbed onto silica, applied to an SPE (Si) and eluted with an ethyl acetate/cyclohexane gradient (0-100% ethyl acetate). The product fractions were reduced to dryness under vacuum and triturated with ether to give N-(6-chloro-4′-{[(cyclopropylmethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide. NMR; δH [2H6]—DMSO 10.10,(1H, s), 8.65,(1H, t), 8.38,(1H, s), 7.94,(2H, d), 7.80,(3H, m), 7.54,(3H, m), 6.98,(1H, s), 3.16,(2H, t), 1.06,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS MH+395/397, retention time 3.32 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH2:17]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH3:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([NH:8][C:9](=[O:10])[N:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:17][CH3:18])([CH3:7])[CH3:6]
Reactant: CC(C)(N=C=O)c1ccc(Cl)c(Cl)c1
Reactant: CCNC1CCCCC1
Agent: [C-]#N
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)NC(C)(C)c1ccc(Cl)c(Cl)c1)C1CCCCC1
Yield: 72.8 %

Procedure:
A solution of 2.3 g of 3,4-dichloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 10 ml of chloroform was added to 1.5 g of N-ethylcyclohexylamine. The solvent was then removed by distillation and the resulting white crystals were recrystallized from a mixture of benzene-n-hexane to obtain 2.6 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:28]2)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: COC(=O)CCC1CNCCO1
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)OC)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 44.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with methyl 3-(morpholin-2-yl)propanoate (0.38 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.53 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=3[CH3:32])[O:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:11]=[C:12]([O:14]C)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(S)C.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][NH:17][C:18]3[C:19]([CH3:33])=[C:20]([CH:29]=[CH:30][C:31]=3[CH3:32])[O:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCS
Product: Cc1ccc(OCC(=O)OC(C)C)c(C)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50793.3 %

Procedure:
To a solution of isopropyl 2-[3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (390 mg, 0.9 mmol, 1.0 eq) in CH2Cl2 (10 mL) at 0° C. was added dropwise ethyl mercaptan (321 mg, 5.2 mmol, 6.0 eq) and AlCl3 (690 mg, 5.2 mmol, 6.0 eq). The reaction mixture was stirred at room temperature for 1 h then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 10:1) to give the title compound as a white solid (200 g, 53%).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCC(C1CCCCC1)n1cccn1
Solvent: Cc1ccccc1
Product: OCCC(C1CCCCC1)n1cccn1
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 152A (2.42 g) in toluene (20 mL) diisobutylaluminum hydride (28.2 mL) was added at −78° C. The reaction mixture was stirred for 60 minutes. The reaction mixture was quenched with methanol (10 mL), 1M aqueous HCl (200 mL) and washed with saturated NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by flash chromotography (silica gel, 10-100% ethyl acetate/hexanes) to provide the title compound.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:44])(=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(OCC)(=O)C.CCCCCC>[CH2:21]([O:44][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCC=CCCCCCCCCCCCCOC(=O)CCCCCCCC=CCCCCCCCC
Yield: 94.5 %

Procedure:
Compound D was prepared from Oleoyl chloride and Erucic acid following the general procedure discussed before and as shown in FIG. 9. Pure compound D was a colorless oil obtained by column chromatography with Ethyl acetate/Hexane=1:40. Reaction conditions for branched derivative compounds D2, D3, and D4 are also shown below.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:22][C:23]([CH2:25]Br)=[CH2:24]>CN(C=O)C.CCOC(C)=O.CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:25][C:23]([Br:22])=[CH2:24])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: C=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(Br)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6.00 g (29.8 mmol) 4-benzyloxy-1H-pyridin-2-one in 30 mL DMF at 0° C. is added 19.4 g (59.6 mmol) cesium carbonate and after 15 min 11.9 g (59.6 mmol) 2,3-dibromo-propene. The reaction mixture is stirred 2 h at RT and is diluted with EtOAc/MeOH and water. The organic phase is washed with water and is dried over MgSO4. After filtration and evaporation of the solvent, the residue is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][S:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:14]1[CH:13]=[C:12]([S:9]([CH2:8][C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[N:3]=[C:2]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:7]=2)(=[O:11])=[O:10])[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A stream of nitrogen was passed through 2-chloro-4-[(3,5-difluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (0.727 g, 1.8 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.513 g, 2.34 mmol) and 2M aqueous sodium carbonate (3.24 mL, 6.48 mmol) in DMF (3.75 mL), DME (5 mL), ethanol (5 mL) and water (12.5 mL) for 15 minutes. The reaction mixture was treated with dichlorobis(triphenylphosphine)palladium(II) (0.063 g, 0.09 mmol) and the mixture was stirred at 80° C. for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-60% ethyl acetate in isohexane, to give the desired product as a yellow solid (0.735 g).