Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(=O)C.O>C(O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reaction time: 0.25 h

Procedure:
30.00 g of 4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-6-nitroquinazoline are suspended in a mixture of 900 ml of ethanol, 120 ml of glacial acetic acid, and 300 ml of water. The suspension is refluxed, producing a clear solution. 17.24 g of iron powder is then carefully added batchwise, while the reaction mixture effervesces each time. About 15 minutes after it has all been added, a precipitate is formed. The reaction mixture is stirred for a further 15 minutes and then evaporated to dryness in vacuo. The residue in the flask is taken up in 1000 ml of methylene chloride/methanol (9:1) and combined with 30 ml of 33% aqueous ammonia solution. The iron slurry is filtered off and washed with methylene chloride:methanol (9:1). The brown filtrate is filtered through a silica gel pack and evaporated to dryness. The residue in the flask is stirred with 60 ml of diethylether, suction filtered and dried in the air.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([CH2:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25]CC)=[O:24])C>C1(C)C=CC=CC=1>[CH:10]1([CH2:16][N:17]2[C:21](=[O:20])[C:22]([C:23]([OH:25])=[O:24])=[CH:28][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]2=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCC1CCCCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: O=C1CCCCCCC1
Solvent: Cc1ccccc1
Product: O=C(O)c1cc2c(n(CC3CCCCC3)c1=O)CCCCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under the nitrogen gas atmosphere, a solution of cyclooctanone (15 g, 118 mmol) and cyclohexylmethylamine (16.1 g, 142 mmol) in toluene (300 mL) was refluxed under azeotropic dehydration for 6 hours. After that, diethyl ethoxymethylenemalonate (24 mL, 142 mmol) was added, and the mixture was further refluxed for 2 hours. After the reaction mixture had been removed by distillation under reduced pressure, the residue was dissolved in the mixed solvent of THF (200 mL) and methanol (200 mL), then a 2M sodium hydroxide aqueous solution was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was removed by distillation under reduced pressure, water was added to the residue and the water layer was washed with diethyl ether one time. Then, after 2 M hydrochloric acid was added to the water layer to acidify it, the water layer was extracted with ethyl acetate. The organic layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and a pale yellow solid (AA01, 21.5 g, 57%, mp: 162-163° C.) was obtained
Reaction SMILES: CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:36]([OH:38])=O)[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH3:39][O:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[NH2:43]>ClCCl>[CH3:39][O:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:36](=[O:38])[C@@H:30]([CH2:31][C:32]([CH3:33])([CH3:34])[CH3:35])[NH:29][C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
N-methylmorpholine (5 equivalents, 6.0 mmol), EDC (2.5 equivalents, 3.0 mmol) and HOBt (2.5 equivalents, 3.0 mmol) are added slowly to a solution of N-(tert-butoxycarbonyl)-3-tert-butyl-D-alanine (1.0 equivalent, 1.2 mmol) and 3-(3-pyridyl)-L-alanine methyl ester (1.0 equivalent, 1.2 mmol) in dry dichloromethane (3 ml) at −30° C. The reaction mixture slowly (approx. 12 h) warms to room temperature, with complete conversion being observed by means of HPLC (method 36). The reaction mixture is worked up by diluting with dichloromethane (20 ml) and washing with saturated sodium bicarbonate solution (10 ml). The organic phase is dried with magnesium sulphate, filtered and concentrated. The crude product is purified by flash chromatography (silica gel, gradient dichloromethane 100% to dichloromethane/methanol: 4/1), resulting in 466 mg (96% of theory) of product.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][O:9][C:10](=[O:28])/[CH:11]=[CH:12]/[C:13]1[CH:27]=[CH:26][C:16]2[NH:17][C:18]([C:20]3([NH3+:25])[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:15]=2[CH:14]=1.[CH:29]1([C:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[N:37]([CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:36]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:29]1([C:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44]([NH:25][C:20]4([C:18]5[NH:17][C:16]6[CH:26]=[CH:27][C:13](/[CH:12]=[CH:11]/[C:10]([O:9][CH3:8])=[O:28])=[CH:14][C:15]=6[N:19]=5)[CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:45])=[CH:41][CH:42]=3)[N:37]([CH2:47][C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:36]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)/C=C/c1ccc2[nH]c(C3([NH3+])CCCC3)nc2c1
Reactant: CN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2[nH]c(C3(NC(=O)c4ccc5c(C6CCCCC6)c(-c6ccccc6)n(CC(=O)N(C)C)c5c4)CCCC3)nc2c1
Reaction time: 8 h

Procedure:
To a solution of 1-{5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-1H-benzimidazol-2-yl}cyclopentanaminium trifluoroacetate (from Step 4, 1 eq), 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Example 1, Step 6, 1 eq) in DMF (0.02 M), HATU (1 eq) and DIPEA (5 eq) were added. The reaction mixture was left at RT with stirring overnight. The resulting mixture was partitioned between EtOAc and hydrochloric acid. The combined EtOAc layers were washed with saturated aqueous NaCl solution, separated, dried over Na2SO4, filtered and evaporated in vacuo to afford methyl (2E)-3-(2-{1-[({3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indol-6-yl}carbonyl)amino]cyclopentyl}-1H-benzimidazol-5-yl)acrylate, which was used without further purification. MS (ES+) m/z 672 (M+H)+.
Reaction SMILES: [N:1]1([C:5]2[S:6][C@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:15][CH2:14][C@H:12]2[O:13][C@H:7]3[C@H:8]([N:9]=[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)[S:6]3)[C@@H:10]([OH:17])[C@@H:11]2[OH:16])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H]3SC(N4CCC4)=N[C@@H]3[C@@H](O)[C@@H]2O)cc1
Yield: 12.7 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5.0 g, 19 mmol) and triethylamine (3.88 g, 38 mmol) in DMF (50 mL) was treated with 4-methylbenzene-1-sulfonyl chloride (4.4 g, 23 mmol) overnight at room temperature. The reaction mixture was quenched by water (100 mL), extracted with dichloromethane (3×80 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 1%-5% methanol in dichloromethane to give crude compound 4 as a light yellow solid (1.0 g). This material was employed in the next step without further purification. (ES, m/z) [M+H]+ 415.0.
Reaction SMILES: O/[CH:2]=[C:3](/[CH2:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)\[C:4]([O:6]C)=O.[C:15](=[NH:38])([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:22][CH:21]=1)[NH2:16].[C:39]([O-:42])([O-])=[O:40].[K+].[K+]>C1(C)C=CC=CC=1>[F:35][C:34]([F:37])([F:36])[C:39]([OH:42])=[O:40].[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][O:17][C:15]3[NH:38][CH:2]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[C:4](=[O:6])[N:16]=3)=[CH:21][CH:22]=2)=[CH:28][C:29]=1[C:34]([F:35])([F:36])[F:37]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C\O)Cc1cnn(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1cc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Product: O=C(O)C(F)(F)F
Temperature: 130 °C
Yield: 33.5 %

Procedure:
To a suspension of methyl (2Z)-3-hydroxy-2-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-propenoate (125 mg, 0.636 mmol) and 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-phenyl)ethyl imidocarbamate (190 mg, 0.530 mmol) in toluene (4 mL) was added K2CO3 (220 mg, 1.589 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (55 mg, 16.78% yield). LCMS: rt=3.45 min, [M+H+]=505
Reaction SMILES: [CH2:1](N)[C:2]#[CH:3].[N:5]1C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:3]([C:13]1[C:12]([Cl:11])=[CH:17][CH:16]=[CH:15][C:14]=1[S:18]([NH2:5])(=[O:20])=[O:19])[C:2]#[CH:1]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: c1ccncc1
Reactant: C#CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCc1c(Cl)cccc1S(N)(=O)=O
Temperature: 4 °C
Reaction time: 12 h

Procedure:
To a stirred solution of propargylamine (0.78 ml, 12.0 mmol) and pyridine (3.0 ml) in CH2Cl2 (30 ml), 4-dimethylaminopyridine (122 mg, 1.0 mmol) and a solution of m-chlorobenzenesulfonyl chloride (2.11 g, 10.0 mmol) in CH2Cl2 are added at 4° C. The reaction mixture is stirred for 30 min at 4° C. and for 12 h at room temperature. The reaction mixture is extracted with CH2Cl2 and aqueous 1 N HCl solution, the organic layer dried over MgSO4, the solvents evaporated and the solid residue suspended in a mixture of hexane/ethyl acetate (1:8), filtered and dried under reduced pressure to yield the title compound as beige solid. 1H-NMR (300 MHz, CDCl3): 7.95-7.9; 7.9-7.75; 7.65-45 (3m, 4H); 4.85 (br.s, 1H); 3.95-3.9 (m, 2H); 2.14 (t, J=2.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(-c3ccccc3)nn2)cc1
Yield: 82.6 %

Procedure:
3-Chloro-6-phenylpyridazine (0.026 moles, 5.0 g), 4-aminothiophenol (0.026 moles, 3.3 g) and potassium carbonate (0.026 moles, 3.6 g) were stirred in 250 ml ethanol for 3 days. The reaction was filtered, concentrated, ethyl acetate added, washed with water and dried over sodium sulfate. The solution was concentrated and the product purified by HPLC over silica gel eluted with 50% ethyl acetate/hexane to yield 3-(4-aminophenylthio)-6-phenylpyridazine 6.0 g, 83%. Mass Spec (FD) 279. Calculated for C16H13N3S: C, 68.79; H, 4.69; N, 15.04. Found: C, 68.87; H, 4.43 N, 15.31.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2N=N1.Cl.[NH2:24][C@H:25]([C:28]1[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=1)[CH2:26][OH:27].C(N(CC)C(C)C)(C)C.[CH2:47]1[CH2:51][O:50][CH2:49][CH2:48]1>O>[OH:27][CH2:26][C@H:25]([NH:24][C:49]([C@H:48]1[CH2:47][C@@H:51]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:50])[C:28]1[CH:29]=[N:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=1
Reactant: On1nnc2ccccc21
Reactant: C1CCOC1
Reactant: N[C@@H](CO)c1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](CO)c1ccc(C(F)(F)F)nc1)[C@H]1C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.39 g, 2.03 mmol) and 1-hydroxybenzotriazole (0.366 g, 2.71 mmol) were added to a stirred mixture of IM46 (0.22 g, 1.36 mmol) and commercially available (R)-2-amino-2-(6-trifluoromethyl-pyridin-3-yl)-ethanol hydrochloride (Supplier Netchem Inc., Catalog No 517882) (0.494 g, 2.03 mmol) and N,N-diisopropylethylamine (0.472 ml, 2.71 mmol) in THF (20 ml). The solution was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc (3×80 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent was evaporated of in vac. The crude product was purified by silica gel chromatography (EtOAc in heptanes 10:1). Yield of Compound 22475 mg (78%). 1H-NMR (500 MHz, DMSO) δ 8.77 (d, 1H), 8.74 (s, 1H), 8.00 (d, 1H), 7.88 (d, 1H), 7.27 (m, 2H), 7.18 (m, 1H), 7.13 (d, 2H), 5.04 (m, 2H), 3.64 (m, 2H), 2.22 (m, 1H), 2.07 (m, 1H), 1.37 (m, 1H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 351.1 (MH+), tR=1.51 min (method A).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=3)=[CH:21][C:20]([C:31]([OH:33])=O)=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17].Cl.[NH:35]1[CH:39]=[CH:38][NH:37][C:36]1=O.CN(C([O:48]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=3)=[CH:21][C:20]([C:31]([N:35]3[CH2:39][C:38](=[O:48])[NH:37][CH2:36]3)=[O:33])=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: COc1cncc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=c1[nH]cc[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cncc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.12 ml (0.70 mmol) of N,N-diisopropylethylamine is added to a solution of 220 mg (0.23 mmol, 37% purity) of the compound of Example 64A, 57 mg (0.47 mmol) of 4-imidazolinone-hydrochloride, and 142 mg (0.38 mmol) of HATU in 6 ml of THF, and the mixture that is obtained is stirred for 20 hours at room temperature. After the further addition of 57 mg (0.47 mmol) of 4-imidazolinone-hydrochloride as well as 89 mg (0.23 mmol) of HATU, stirring is continued for 16 hours at 60° C. The crude product is separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). 39 mg (35% of theory, 88% purity) of the title compound is obtained.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[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][CH3:15].S(Cl)([Cl:31])=O>ClCCl>[CH2:1]([C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21]([Cl:31])=[O:22])[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][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)Cl)c1

Procedure:
2-(3-Pentadecylphenoxy)butanoic acid (4.18 g, 0.01 mol) (CAS Registry Number 14230-52-5) and thionyl chloride (30 ml) were heated under reflux on a steam-bath for 1 h. The resulting yellow solution was allowed to cool before being distilled under reduced pressure to leave a yellow oil. The oil was dissolved in dichloromethane (50 ml) and the solution was distilled under reduced pressure to remove volatiles. The residual 2-(3-pentadecylphenoxy)butanoyl chloride was used without further purification.
Reaction SMILES: N[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27].N(OC(C)(C)C)=O.[ClH:39]>C(#N)C.[Cu](Cl)Cl>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([CH2:27][CH:26]([Cl:39])[C:25]([O:29][CH2:30][CH3:31])=[O:28])[C:7]=1[O:8][CH3:9]
Reactant: C=CC(=O)OCC
Reactant: Cl
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)C(Cl)Cc1c(OC)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reaction time: 16 h

Procedure:
A solution of 3-(2-amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)pyrimidinedione (0.94 g, 2.56 mmol) in acetonitrile (3 ml) was slowly added to an acetonitrile (9 ml) solution of ethyl acrylate (6 ml), tert-butyl nitrite (0.41 g, 3.97 mmol), and copper (II) chloride (0.42 g, 3.12 mmol) at −20° C. After stirred for 16 hr (−20° C. to room temperature), the mixture was poured into cold 5% hydrochloric acid (30 ml) and extracted with ethyl acetate (20 ml ×3), the organic phase was washed with cold 5% NaHCO3 and brine, dried over Na2SO4. Column chromatography was used for purification (silica gel, hexane/ether=9/1) which also isolated two isomers. Yield: isomer-1 (eluted earlier), 0.23 g, 0.47 mmol; isomer-2 (eluted later), 0.14 g, 0.29 mmol.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[C:6]([F:15])[CH:5]=1.Br[CH2:17][C:18]([OH:20])=[O:19]>CN(C)C(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([O:14][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13]2)=[C:6]([F:15])[CH:5]=1
Reactant: OC1(c2ccc(Br)cc2F)CCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COC1(c2ccc(Br)cc2F)CCC1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
A 50 mL round-bottomed flask was charged with NaH (361 mg, 9.04 mmol) and N,N-dimethylacetamide (5 mL). A solution of the product from Example 60A (443 mg, 1.808 mmol) in N,N-dimethylacetamide (5 mL) was added dropwise, and the reaction was stirred at 22° C. for 30 min. A solution of 2-bromoacetic acid (502 mg, 3.62 mmol) in N,N-dimethylacetamide (5 mL) was added dropwise. The reaction was stirred at 22° C. for 16 hours and was then quenched by the slow addition of water (15 mL). The aqueous was extracted with 1:1 diethyl ether/hexanes (2×20 mL), and the organics discarded. The aqueous layer was acidified to pH 1 with 1M HQ and extracted with ethyl acetate (2×75 mL). The combined organics were washed with water (4×20 mL) and brine (1×20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.70 (m, 1H), 1.91-2.10 (m, 1H), 2.34-2.47 (m, 4H), 3.65 (s, 2H), 7.34-7.43 (m, 2H), 7.49-7.53 (m 1H), 12.45 (s, 1H).
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[C:9]([O:10][CH3:11])=[CH:8][N:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14]C=2)[N:5]=1.Cl.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:40]=[CH:39][C:29]([C:30]([NH:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[O:31])=[CH:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1.C([N:43](CC)CC)C>CN(C=O)C>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:40]=[CH:39][C:29]([C:30]([NH:32][CH:33]3[CH2:34][CH2:35][N:36]([C:4]4[C:9]([O:10][CH3:11])=[CH:8][N:7]=[C:6]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][N:43]=5)[N:5]=4)[CH2:37][CH2:38]3)=[O:31])=[CH:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cnc(-c2ccccc2)nc1Cl
Reactant: CCN(CC)CC
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cnc(-c2ccccn2)nc1N1CCC(NC(=O)c2ccc(-c3cccc(F)c3)nc2)CC1
Temperature: 87.5 °C

Procedure:
To a vial containing CsF (60-85 mgs, 5-7 eqs) was added (0.2 mL, 0.08 mmol) of a solution of 4-chloro-5-methoxy-2-phenylpyrimidine in DMF followed by addition of (0.22 mL, 0.088 mmol) of 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide-HCl salt in DMF and triethylamine (2-3 eq). The reaction mixture was heated to 85-90° C. for 24 hrs and then allowed to cool to room temperature. The crude reaction mixture was then filtered and purified by RP-HPLC to give the desired product. 1H NMR (400 MHz, DMSO-d6) □ ppm 1.63-1.73 (m, 2H) 1.96 (d, J=10.25 Hz, 2H) 3.11-3.19 (m, 2H) 3.94 (s, 3 H) 4.18 (d, J=7.69 Hz, 1H) 4.64 (d, J=12.81 Hz, 2H) 7.31 (td, J=8.33, 2.38 Hz, 1H) 7.43 (d, J=5.12 Hz, 1 H) 7.53-7.59 (m, 1H) 7.87-7.97 (m, 2H) 8.00 (d, J=7.69 Hz, 1H) 8.12 (d, J=8.42 Hz, 1H) 8.20 (s, 1H) 8.26 (d, J=8.05 Hz, 1H) 8.29 (dd, J=8.42, 1.83 Hz, 1H) 8.50 (d, J=7.69 Hz, 1H) 8.68 (d, J=4.39 Hz, 1H) 9.08 (s, 1H); LC/MS(ES+)=485.5 observed, 485.21 expected.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:9]=3)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cc3cc(Br)ccc3[nH]2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-c2cc3cc(-c4ccccc4)ccc3[nH]2)cc1
Temperature: 160 °C
Yield: 10.6 %

Procedure:
To a suspension of 5-bromo-2-(4-chlorophenyl)-1H-indole (200 mg, 0.65 mmol) in dioxane/water 4:1 v/v (5 mL) was added phenylboronic acid (87 mg, 0.72 mmol) and a few milligrams of tetrakis(triphenylphosphine)palladium(0). The resulting suspension was heated in the microwave at 160° C. for 15 min. After cooling, the reaction was poured into water to give a precipitate, which was filtered off and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v), followed by a recrystallisation from hot ethyl acetate to afford 21 mg (11%) of the title compound (LCMS RT=8.54 min, MH+ 304.1)