Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[NH2:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][CH2:30][CH2:31][CH2:32][PH:33](=[O:52])[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[C:41]([B:43]3[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:51])([CH3:50])[O:44]3)[CH:40]=[N:39]2)=[CH:27][C:26]=1[O:55][CH3:56].C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:24][C:25]3[CH:54]=[CH:53][C:28]([CH2:29][CH2:30][CH2:31][CH2:32][PH:33](=[O:52])[O:34][CH2:35][CH2:36][CH2:37][N:38]4[CH:42]=[C:41]([B:43]5[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:50])([CH3:51])[O:44]5)[CH:40]=[N:39]4)=[CH:27][C:26]=3[O:55][CH3:56])[N:14]=2)=[C:6]([C:7](=[O:8])[NH:9][CH3:10])[CH:11]=1
Reactant: COc1cc(CCCC[PH](=O)OCCCn2cc(B3OC(C)(C)C(C)(C)O3)cn2)ccc1N
Reactant: CNC(=O)c1cc(Br)ccc1Nc1nc(Cl)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-bromo-2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 66B, 150.5 mg, 0.3674 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propyl (4-amino-3-methoxybenzyl)propylphosphinate (Compound 66C, 175.4 mg, 0.3674 mmol) in TFE (5.0 mL) was charged with TFA (0.0602 mL). The reaction mixture was stirred at 50° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to a light yellow oil and purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→90:10) as eluent to afford the racemic title compound as 0.245 g of a white solid (78%). MS (ESI): m/z 850.91/852.88 [M+H]+. UPLC: tR=1.52 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23](I)=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([SH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.CO.C(Cl)Cl.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([S:37][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2ccccc12
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3cc(I)ccc3o2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2nc3cc(Sc4cccc5ccccc45)ccc3o2)CC1
Temperature: 90 °C
Yield: 31 %

Procedure:
A mixture of 4-(5-iodobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester, prepared in Example 2 (1.48 mmol theory), 1-napthalenethiol (0.237 g, 1.48 mmol), CuI (0.042 g, 0.22 mmol), and K2CO3 (0.409 g, 2.96 mmol) in isopropanol was heated at 90° C. overnight, diluted with 20% MeOH in CH2Cl2, and filtered through a pad of silica gel. The filtrate was concentrated to dryness. The resultant residue was purified by chromatography with 5% MeOH in CH2Cl2 to provide the title compound (230 mg, 31% overall yield from 4-benzoxazol-2-yl-piperazine-1-carboxylic acid benzyl ester), characterized by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]>CN(C=O)C.[Cu]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: [Cu]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
The mixture of 1,4-dibromo-2-nitro-benzene (25 g, 89 mmol) and copper powder (12.5 g, 197 mmol) in DMF (150 ml) was heated at 137 C for 2 hours. The mixture was cooled to 25° C. and was quenched with water. The mixture was extracted with EtOAc (2×). The combined organic solution was washed with water and brine and was dried with Na2SO4. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4′-dibromo-2,2′-dinitro-biphenyl (13.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17].[C:19]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:19])[CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)nc(C)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(Cl)nc(C)cc2c1=O
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Ethyl 8-chloro-6-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxylate (Preparation 43, 1.86 g) is dissolved in DMF (20 mL) and K2CO3 (2.4 g) is added followed by iodomethane (1.28 g) at room temperature. The mixture is stirred for 5 hours and then added to water (120 mL). The solid is washed with additional water, collected and dried under high vacuum to obtain 0.72 g (37%) of the title compound as a pale green powder. Physical characteristics: MS (ESI+) m/z 281 (M+H).
Reaction SMILES: [C:1]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(OC(Cl)=O)C(C)C.Cl.[C:26]([O:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1.CN1CCOCC1>[C:26]([O:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:14](=[O:16])[CH2:13][N:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:12])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
4.5 g of CBZ-sarcosine is dissolved in 100 ml tetrahydrofuran and 2.4 ml of n-methylmorpholine is added. The reaction mixture is cooled to -10° C. and stirred while 2.6 ml of isobutylchloroformate is added. After 5 minutes of additional stirring at -10° C. 4.15 g L-proline-t-butylester hydrochloride in 100 ml of tetrahydrofuran and 3.0 ml of n-methylmorpholine are added to the reaction mixture. The reaction mixture is stirred overnight and slowly warmed to room temperature. The solvent is evaporated under reduced pressure at 30° C. and the residue is dissolved in 600 ml ethylacetate. The ethylacetate layer is washed with (3×150 ml), lN sodium hydroxide, water (1×200 ml) 10% citric acid (3×150 ml), and water (3×150 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide carbobenzoxysarcosyl-proline-t-butyl ester (CBZ-Sar-L-Pro-O-t-But). 6.5 g of this material is dissolved in 15 ml of methylene chloride and 25 ml of trifluoroacetic acid is then added. The reaction mixture is kept at room temperature for 45 minutes and then the solvent is evaporated under reduced pressure at 30° C. The residue is triturated with hexane (3×50 ml) and the hexane removed by decantation. The residue is evaporated from (2×50 ml) of benzene to provide an oily residue which is carbobenzoxysarcosyl-L-proline (CBZ-Sar-L-Pro). 5.4 g of this material and 3.45 g of N-hydroxysuccinimide are dissolved in 100 ml of tetrahydrofuran and cooled to 0° C. To this cooled reaction mixture is added 4.12 g of dicyclohexylcarbodiimide. The reaction mixture is stirred overnight at 4° C. and the solvent is evaporated under reduced pressure. The residue is dissolved in 400 ml of ethylacetate and the dicyclohexyl urea is filtered off. The filtrate is washed with lN-hydrochloric acid (3×100 ml), water (1×100 ml), saturated sodium bicarbonate solution (2×100 ml) and water (2×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated under reduced pressure to provide carbobenzoxy-sarcosyl-L-proline-succinimidyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=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.[F:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH2:67][NH2:68]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[F:60])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: NCc1ccccc1F
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2F)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.17 mL, 0.96 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 1-(2-Fluorophenyl)methanamine (60 mg, 0.48 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (189 mg) as a light yellow solid. LC-MS (ES) m/z=463 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC.[Li+].[Cl-]>CN(C=O)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>[Br:8][C:7]1[C:2]([CH:9]=[CH2:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ncccc1Br
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 2,3-dibromopyridine (2.0 g, 8.44 mmol) in DMF (10 mL) was treated with tributyl(vinyl)tin (2.94 g, 9.29 mmol), LiCl (1.07 g, 25.32 mmol), and PdCl2(PPh3)2 (0.296 g, 0.422 mmol). The reaction mixture was heated at 100° C. for 18 hours. The mixture was extracted with hexanes (3×50 mL). The combined hexane layers were extracted with 1N HCl. The aqueous layer was neutralized with 1N NaOH, extracted with hexanes, and the extracts were dried (MgSO4), filtered, and concentrated to provide the desired product as a yellowish oil (0.83 g, 53% yield). MS m/z 184(MH+); 1H NMR (300 MHz, CD3OD) δ 5.53 (dd, J=10.80, 2.01 Hz, 1H), 6.33 (dd, J=16.83, 1.83 Hz, 1H), 7.08–7.26 (m, 2H), 7.96 (dd, J=8.05, 1.46 Hz, 1H), 8.44 (dd, J=4.76, 1.46 Hz, 1H); 13C NMR (300 MHz, CD3OD) δ 121.9, 122.4, 125.7, 134.9, 142.8, 149.5, 154.5.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].C([Li])CCC.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[C:39]([OH:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClCCl>C1COCC1>[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[CH:2][CH2:3][CH3:4])=[C:39]([OH:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a flame dried 500 mL 3-neck flask under an atmosphere of argon, was charged n-propyltriphenylphosphonium bromide (12.66 g, 32.85 mmol) dissolved in anhydrous THF (85 mL), followed by the dropwise addition of n-butyllithium 16.4 mL, 26.28 mmol). The dark red mixture was stirred at ambient temperature for 1 h. 15 min. Next 4-benzyloxy-2-hydroxybenzaldehyde (1.5 g, 6.57 mmol) (Synth. Commun., 26(3), 593-601, (1996) was added followed by the addition of anhydrous dichloromethane (27 mL). The mixture was stirred at ambient temperature for 18 h. The solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water (500 mL each). The organic layer was washed with brine (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified using the Biotage FlashElute chromatography system using a 65M normal phase cartridge, eluting with 15% ethyl acetate/Hex to give a yellow solid (1.50 g, 90%). 1H NMR (400 MHz, CDCl3) δ7.43-7.30 (m, 5H), 7.19 (d, J=8.3 Hz, 1H), 6.52 (dd, J=8.8, 2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.43 (s, 1H), 6.14-6.07 (m, 1H), 5.03 (s, 2H), 4.98 (s, 1H), 2.25 (quintet, J=7.6 Hz, 2H), 1.09 (t, J=7.3 Hz, 3H), MS (ES) m/e 255 (M+1).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH2:10])=[S:9])[CH2:3][CH2:2]1.Br[CH:12]([CH2:18][CH3:19])[C:13](OCC)=[O:14]>>[CH:4]1([NH:7][C:8]2[S:9][CH:12]([CH2:18][CH3:19])[C:13](=[O:14])[N:10]=2)[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C(Br)CC
Reactant: NC(=S)NC1CCCCC1
Product: CCC1SC(NC2CCCCC2)=NC1=O

Procedure:
Synthesis was performed from n-cyclohexylthiourea and ethyl 2-bromobutyrate according to Method C. Gave 201 mg (75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][OH:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[C:19]([C:20]([NH:22][NH:23][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][OH:14])=[O:21])=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)O
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (500 mg, 2.4 mmol) and 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (2.6 mmol, 1.1 equiv.) in DMF (10 mL), DIPEA (12 mmol, 5 equiv.) and HATU (2.6 mmol, 1.1 equiv.) were added and stirred overnight at room temperature. The reaction mass was concentrated under reduced pressure to remove excess of solvent present. Diluted the residue with EtOAc and washed water followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get tert-butyl (1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-3-hydroxy-1-oxopropan-2-yl)carbamate (53).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2=[N:4][CH:3]=1.B.C1COCC1.Cl>C1COCC1.O1CCOCC1>[Br:1][C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([CH2:16][NH2:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:5]2=[N:4][CH:3]=1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)COc1c(CN)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (477 mg, 1.0 mmol, prepared according to Example 35, Step 20.2) in anhydrous THF (12 mL) were added a BH3.THF complex (1.0 M solution in THF, 4.5 mL, 4.5 mmol) followed by a 4M HCl solution in dioxane (10 drops) at RT. The reaction mixture was heated at 50° C. and stirred for 3 h, then cooled to 0° C. (ice bath), quenched by the cautious addition of a 2M HCl solution in water (10 mL) and poured into water (100 mL). The aqueous mixture was washed with Et2O (2×30 mL) then basified to pH 10 by the addition of a 2M Na2cO3 solution in water and extracted with DCM (2×30 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to dryness to yield the crude C-[3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridin-7-yl]-methylamine intermediate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[F:24])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.B(OC)(OC)[O:37]C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[F:24])[CH:5]=[C:6]([F:8])[C:7]=1[OH:37]
Reactant: COB(OC)OC
Reactant: CCCc1ccc(-c2ccc(-c3cc(F)cc(F)c3)c(F)c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(-c3cc(F)c(O)c(F)c3)c(F)c2)cc1
Temperature: -40 °C
Yield: 74.4 %

Procedure:
Under a nitrogen atmosphere, the 3,5-difluoro-[2-fluoro-4-(4-propylphenyl)phenyl]benzene (18.7 g) obtained in the process (1-1) was dissolved in THF (90 mL), and the solution was cooled to −40° C. or lower. Then, 1.6 mol/L of an n-butyllithium/hexane solution (40 mL) was added thereto at a rate which did not allow the internal temperature to be −35° C. or higher, and the product was stirred at −40° C. for an hour. Then, trimethyl borate (7.1 g) was added thereto at −40° C. at a rate which did not allow the internal temperature to be −35° C. or higher. The temperature was slowly increased to room temperature, the product was further stirred for 30 minutes at room temperature, 10% hydrochloric acid (50 mL) was subsequently added thereto under cooling with ice to separate the organic layer, and the organic layer was washed with a saturated salt solution. Then, a 30% hydrogen peroxide solution (8.4 g) was slowly added thereto, and then the product was stirred at 40° C. for 14 hours. The product was cooled with ice, and a 10% aqueous sodium sulfite solution was added thereto at a rate which did not allow the internal temperature to exceed 20° C., thereby separating the organic layer. Toluene was added to the water layer for extraction, the organic layer was added thereto and then washed with a saturated salt solution, and sodium sulfate was added thereto for dehydration. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography and then recrystallized from hexane, thereby yielding 14.6 g of 2,6-difluoro-4-[2-fluoro-4-(4-propylphenyl)phenyl]phenol (A).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[C:37]=[O:39]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCN)c2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCN=C=O)c2)n1
Reaction time: 0.5 h

Procedure:
Methyl 6-(3-(6-aminohexyloxy)phenyl)picolinate dihydrochloride (19) (40 mg, 0.10 mmol) and DIEA (34 μL, 26 mg, 0.20 mmol) were dissolved in CHCl3 (0.7 mL). Triphosgene (14 mg, 0.047 mmol) was dissolved in CHCl3 (0.3 mL). The solutions were combined and a second portion of DIEA (34 μL, 26 mg, 0.20 mmol) was immediately added. The mixture was left to stand 30 min at RT and evaporated. The residue was dissolved in ethyl acetate and the precipitated DIEA hydrochloride was filtered off. The solvent was evaporated and the crude isocyanate (20) was used directly for the next step.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[N:22]([CH:24]=[CH:25][CH:26]=3)[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[N:22]([CH:24]=[CH:25][CH:26]=3)[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cn3cccc3cn2)oc2ccc(O)cc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CC(C)(C)ON=c1cc(-c2cn3cccc3cn2)oc2ccc(OCCN3CCOCC3)cc12
Yield: 68 %

Procedure:
6-(2-Morpholin-4-yl-ethoxy)-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 68% yield using the procedure described in example 85A, starting from 6-Hydroxy-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one O-tert-butyl-oxime (example 123B) and 4-(2-chloroethyl) morpholine hydrochloride. The title compound was isolated as a beige solid.
Reaction SMILES: [C:1]1([N:7]2[C:10](=[O:11])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH:20][CH3:21]>C(#N)C>[CH3:19][N:20]([CH3:21])[C:10]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:9][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:18])=[O:11]
Reactant: CNC
Reactant: O=C1N(c2ccccc2)C(=O)N1c1ccccc1
Solvent: CC#N
Product: CN(C)C(=O)N(C(=O)Nc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
In 30 ml of acetonitrile, 0.025 mole of 1,3-diphenyl-1,3-diazetidine-2,4-dione was added, then 4.5 ml (0.05 mole) of dimethylamine aqueous solution (50%) was added dropwise under stirring. The reaction was continued at 50° C. for 0.5 hours and the solvent was removed by distillation under a reduced pressure to obtain a residue. The residue was recrystallized from ethanol to obtain 5.4 g (yield 76%) of 1,1-dimethyl-3,5-diphenylbiuret having a melting point of 105°-107° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:34][C:35]#[N:36]>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:34][C:35]#[N:36])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC#N)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a yellow oil (54%).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.I[CH:14]([CH2:19][C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][CH2:17][OH:18].P(O)(O)O.C(N(CC)CC)C>O1CCOCC1>[F:31][C:20]([F:32])([C:21]([F:29])([F:30])[C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[CH2:19][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: OCCCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: OP(O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: OCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A solution of AIBN (4.9 g, 30 mmol) in dioxane (150 cm3) was added dropwise into a solution of 4iodo-6,6,7,7,8,8,9,9,9-nonafluorononan-1-ol (Preparation 1B, 25 g, 58 mmol), phosphorous acid (19.1 g, 0.29 mol) and triethylamine (32.3 g, 0.32 mol) in dioxane (150 cm3) under an atmosphere of nitrogen during reflux. After addition, the reaction mixture was refluxed for a period of time until the GLC analysis revealed a complete reaction (usually an hour). The crude product was extracted into diethyl ether (3×50 cm3) and dried (MgSO4). The solvent was removed in vacuo and the pure product was obtained by reduced pressure distillation as a colourless liquid.