Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16](O)=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][C:25]=1[Cl:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:34][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:24]=1[CH2:23][NH:22][C:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[N:7]([CH2:6][C:5]1[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:8]=[CH:9]2)=[O:17])[C:28]([OH:30])=[O:29]
Reactant: O=C(O)c1cccc2ccn(Cc3ccc(Cl)cc3)c12
Reactant: COC(=O)c1ccc(CN)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CNC(=O)c2cccc3ccn(Cc4ccc(Cl)cc4)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.6 %

Procedure:
To a mixture of 1-(4-chlorobenzyl)-1H-indole-7-carboxylic acid (0.20 g), methyl 4-(aminomethyl)-3-chlorobenzoate hydrochloride (0.18 g), and HATU (0.32 g) in DMF (4.0 mL) was added diisopropylethylamine (0.29 ml) under ice-cooling, followed by stirring at room temperature for 14 hours. After ice-cooled again, a 5% aqueous citric acid solution (8.0 mL) was added thereto, and the precipitated solid was collected by filtration, sequentially washed with water and diisopropylether, and dried at 60° C. under reduced pressure. To the obtained solid were added methanol (3.0 mL), THF (3.0 mL), and a 1 M aqueous sodium hydroxide solution (2.0 mL), followed by stirring at 60° C. for 2 hours. The reaction mixture was left to be cooled, a 10% aqueous citric acid solution (5.0 mL) was added thereto, and the precipitated solid was collected by filtration, washed with water, and dried at 60° C. under reduced pressure to obtain 3-chloro-4-[({[1-(4-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)methyl]benzoic acid (0.24 g).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[CH:35]1[CH2:37][CH2:36]1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH:35]3[CH2:37][CH2:36]3)[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: Nc1ncnc(Cl)c1C1CC1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C4CC4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-cyclopropyl-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=487, obsd=487). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.46 (d, J=5.2 Hz, 1H), 6.17 (s, 2H), 4.19 (d, J=12.9 Hz, 2H), 3.92 (t, J=6.1 Hz, 2H), 3.12 (t, J=6.7 Hz, 4H), 3.05-2.88 (m, 4H), 2.72 (t, J=6.1 Hz, 2H), 1.98-1.82 (m, 6H), 1.50 (p, J=6.7 Hz, 1H), 1.25 (dd, J=6.9, 1.3 Hz, 6H), 1.02 (d, J=8.1 Hz, 2H), 0.43 (d, J=5.2 Hz, 2H).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([C:30](=[O:32])[CH3:31])=[C:25]([O:33][CH3:34])[C:24]=1I>CN(C)C=O.[Zn].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].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:30]([C:26]1[C:25]([O:33][CH3:34])=[C:24]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:23]([Cl:22])=[C:28]([Cl:29])[CH:27]=1)(=[O:32])[CH3:31]
Reactant: COc1c(C(C)=O)cc(Cl)c(Cl)c1I
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Zinc (4.5 g, 69 mmol) was suspended with 1,2-dibromoethane (420 μL, 4.9 mmol) in N,N-dimethylformamide (54 mL). The mixture was heated at 70° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (620 μL, 4.9 mmol) was added dropwise and stirring was continued for 1 h. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (17 g, 61 mmol) in N,N-dimethylformamide (30 mL) was then added and the mixture was heated at 40° C. for 1 h before a mixture of 1-(4,5-dichloro-3-iodo-2-methoxyphenyl)ethanone (14 g, 41 mmol), tris(dibenzylideneacetone)dipalladium(0) (710 mg, 0.77 mmol) and tri-(2-furyl)phosphine (360 mg, 1.6 mmol) in N,N-dimethylformamide (120 mL) was added quickly. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with water, dried with magnesium sulfate, filtered, and concentrated to a crude residue that was purified by flash column chromatography using ethyl acetate in hexanes (0%-25%) to give the desired product (12 g, 77%). LCMS for C17H21Cl2NO4Na (M+Na)+: m/z=396.1; Found: 396.0.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]([F:24])=[CH:13][C:14]([Cl:23])=[C:15]([CH:22]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>C(C(C)=O)C>[C:1]([NH:10][C:11]1[C:12]([F:24])=[CH:13][C:14]([Cl:23])=[C:15]([CH:22]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCC(C)=O
Product: CC(C)OC(=O)c1cc(NC(=O)c2ccccc2)c(F)cc1Cl
Yield: 90 %

Procedure:
A solution of benzoyl chloride (2.94 g, 0.021 mole) and 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (4.62 g, 0.020 mole) in methyl ethyl ketone (50 ml) was stirred at room temperature for 3 days. Evaporation of the solvent and crystallization of the solid residue from ethyl ether gave colorless needles, m.p. 117°-119° C. (6 g, 90% yield).
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:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:29]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCCl
Reactant: C1CCCNCC1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCCCCC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
300 g of 4-Chloro-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide and 78 mg azepane were dissolved in 5 ml THF and purged with nitrogen. 0.25 ml DIEA was added and the mixture was stirred at 70° C. for 2 days. The mixture was then diluted with 20 ml ethyl acetate, washed with water and brine and dried over Na2SO4. The resulting solids were flash chromatographed with 0-4% methanol in chloroform. The product was dissolved in CH2Cl2 and treated with excess HCl and ether, then evaporated to dryness to give 115 mg of 4-Azepan-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide (33% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C[Mg+].[Br-].[CH3:17]COC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:17])[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: CCOC(C)=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen, a solution of the 3-bromo-4,5-dimethoxybenzaldehyde (2.45 g; 10 mmol) in dry THF (10 ml) was added via syringe through a septum to a cold (ice-bath) solution of MeMgBr (15 mmol; 5.0 ml of 3.0 M Et2O solution) diluted with 10 ml dry THF. After the addition, the mixture was stirred for 10 minutes at 0° C., then for 1 hour at room temperatures. TLC (Hex:EtOAc=3:1) indicated complete disappearance of the reactant and a new product spot with lower Rf (0.25 vs 0.5).
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][C:2]1([CH3:9])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH3:8])(=[O:23])[CH3:22]
Reactant: CC1C(=O)C=CC1(C)O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1(C)C=CC(=O)C1C

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2,3-dimethyl-4-cyclopentenone (12.6 g), p-toluenesulfonic acid (0.5 g) and acetic anhydride (30 g) were charged, and the resultant mixture was stirred at 80°-100° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 2 to give 16.2 g of dl-3-acetoxy-2,3-dimethyl-4-cyclopentenone. Yield, 96.5%. B.P., 52°-55° C./0.4-0.5 mmHg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([Cl:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.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.[Cu]I>[Cl:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][CH:25]=1)[CH2:15]2
Reactant: C#CCN1CCN(C)CC1
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.046 mL, 0.3 mmol), 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.23 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.075 g, 71%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:13]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: O=C(OCCO)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
2-Benzoyloxyethyl oleate was prepared by the procedure of Example 1 from 16 gms (0.1 mole) of ethylene glycol monobenzoate and 30 gms (0.1 mole) of oleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1.C(N(S(F)(F)[F:20])CC)C>>[Cl:1][C:2]1[C:7]([C:8]2([F:20])[CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(C2(O)COC2)c(Cl)n1
Product: Cc1ccc(C2(F)COC2)c(Cl)n1
Yield: 56 %

Procedure:
In analogy to the procedure described in Example 130 b), 3-(2-chloro-6-methylpyridin-3-yl)oxetan-3-ol (Example 134 a, 1.5 g, 7.51 mmol) was reacted with diethylaminosulfur trifluoride to obtain the title compound (850 mg, 56%) as colorless liquid, MS (ESI): m/e=202.1 [MH+].
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:52]([F:55])([F:54])[F:53])=[C:15]([N:17]2[C:21](=[O:22])[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36](=[O:46])(=[O:45])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:26][C:25]=3[F:47])[C:19]([CH2:48][CH2:49][CH2:50][CH3:51])=[N:18]2)[CH:16]=1>>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:52]([F:53])([F:54])[F:55])=[C:15]([N:17]2[C:21](=[O:22])[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36](=[O:45])(=[O:46])[NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[CH:26][C:25]=3[F:47])[C:19]([CH2:48][CH2:49][CH2:50][CH3:51])=[N:18]2)[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Product: CCCCc1nn(-c2cc(NC(=O)c3ccccc3)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 95 %

Procedure:
Benzoyl chloride was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 33, Step D) according to the procedure of Example 26 to give a 95% yield of the title compound as a white solid, mp 117°-120° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 774 (M+Li)+.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:16]([CH2:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)[CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)cc2)C(C)=O)cc1

Procedure:
The title compound was prepared following the procedure G using methyl (4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenoxy)acetate and acetyl chloride (purification by flash chromatography on SiO2, c-Hex/EtOAc 9:1) as a colorless oil (26%). M+ (ESI): 464.3. HPLC, Rt: 5.6 min (purity: 100%). 1H NMR (CDCl3) δ: 7.40 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.17-7.05 (m, 4H), 6.91 (d, J=8.7 Hz. 1H), 6.86 (d, J=8.3 Hz, 1H), 4.65 (s, 1H), 4.63 (s, 1H), 4.54 (s, 1H), 4.51 (s, 1H), 4.40 (s, 1H), 4.35 (s, 1H), 3.83 (s, 1.5H), 3.82 (s, 1.5H), 2.41 (t, J=7.2 Hz, 1H), 2.40 (t, J=7.2 Hz, 1H), 2.22 (s, 1.5H), 2.18 (s, 1.5 H), 1.61 (m, 2H), 1.45 (m, 2H), 1.30 (brs, 8H), 0.90 (t, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:23](O)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:5]([O:11][CH2:23][CH3:24])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(F)c(-c2cncc(S(C)(=O)=O)c2)c1O
Reactant: CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 1-{5-chloro-4-fluoro-2-hydroxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone (1.3 g, 3.6 mmol) in THF (32 mL) was treated with ethanol (0.28 mL, 4.73 mmol) and triphenylphosphine (1.3 g, 5.1 mmol). The reaction mixture was cooled to 0° C., treated with diisopropyl azodicarboxylate (1.1 mL, 5.5 mmol) dropwise, and stirred at 20° C. for 1 hour. The reaction mixture was concentrated to remove most of the THF, diluted with EtOAc, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to a crude residue which was purified by flash column chromatography using EtOAc in hexanes (15%-65%) to give the desired product (1.2 g, 87%). LCMS for C16H16ClFNO4S (M+H)+: m/z=372.0. Found: 372.1.
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>C(C(C)=O)C>[CH:21]1([C@@:7]([OH:8])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][N:38]5[C:46](=[O:47])[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[C:39]5=[O:48])=[CH:34][CH:35]=4)[CH2:17][CH2:16]3)[N:10]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OC(c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Solvent: CCC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
Cyclohexyl-phenyl-(1-piperidin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-methanol (Preparation 4, 0.40 g, 1.13 mmol) and 2-{2-[4-(2-Bromo-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 11, 0.404 g, 1.13 mmol) and diisopropylethylamine (0.59 ml, 3.38 mmol) were dissolved in methyl ethyl ketone (8 mL). After stirring at 90° C. for 24 hours the reaction was allowed to cool slowly to room temperature. Crystallisation occured and the resulting solid was collected by filtration and dried in vacuo to yield the title compound as a cream coloured solid, in 74% yield, 0.532 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:42]1[CH2:51][C@H:50]([OH:52])[CH2:49][C@H:43]1[C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][OH:39])[CH:31]=[CH:30][C:29]=1[O:40][CH3:41]>CO.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:26])[F:25])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:42]1[CH2:51][C@H:50]([OH:52])[CH2:49][C@H:43]1[C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:31]=[CH:30][C:29]=1[O:40][CH3:41]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=CCCO)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCCCCO)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Under hydrogen atmosphere, suspension of 200 mg of the compound obtained in Example 262 and 20 mg of 5% palladium-carbon in MeOH (2 ml) was stirred at room temperature for one hour. The insoluble matter was separated by filtration with celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=30/1 to 15/1; v/v) to obtain 86 mg of the title compound (amorphous).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:25])([F:24])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)[OH:12].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([O:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[C:10]([F:9])([F:25])[F:24])[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC(c1ccccc1-n1cccn1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-n1cccn1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 112.8 %

Procedure:
4,6-Dichloro pyrimidine (0.082 g, 0.55 mmol), 2,2,2-trifluoro-1-(2-pyrazol-1-yl-phenyl)-ethanol (0.121 g, 0.50 mmol), NaH (0.03g, 0.78 mmol) were added to anhydrous THF (10 ml) under nitrogen atmosphere. The reaction was stirred at 40-45° C. for 6 h, and then was cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated to give crude 4-chloro-6-[2,2,2-trifluoro-1-(2-pyrazol-1-yl-phenyl)-ethoxy]-pyrimidine (0.20 g, >90% pure by LCMS), which was directly used in the following step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[N:6][CH:7]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=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+]>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].O1CCOCC1>[Br:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]3[CH3:21])=[N:6][CH:7]=2)[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(N)cn1
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: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Temperature: 90 °C
Yield: 92.2 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 230c (1.25 g, 4.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (3.4 g, 12.9 mmol), Pd2(dba)3 (394 mg, 0.43 mmol), Xantphos (497 mg, 0.86 mmol), Cs2CO3 (4.7 g, 14.6 mmol), and 1,4-dioxane (80 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 230d (1.9 g, 72%). MS: [M+H]+ 481.2.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:7][C:6]=1[N+:18]([O-])=O>C(O)C.O.[Fe]>[NH2:18][C:6]1[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10][C:5]=1[O:4][CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])c(OC)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(N)c(OC)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Iron (3.72 g) and ammonium chloride (7.13 g) were added to a solution of ethyl (E)-3-(6-methoxy-5-nitropyridin-2-yl)acrylate (2.1 g) in ethanol (100 mL) and water (20 mL). The reaction solution was stirred at 100° C. for one hour and then left to cool to room temperature. The reaction solution was filtered through celite. Ethyl acetate was added and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.85 g of the title compound. The property values of the compound are as follows.