Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[H][H]>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: COC(=O)/C=C/c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 3 h

Procedure:
A slurry of (E)-methyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)acrylate (0.116 g, 0.269 mmol) and Pd/C 10%, 50% water (0.115 g, 0.108 mmol) in 2 mL THF was treated with a hydrogen balloon with rapid stirring for 3 h. The reaction mixture was flushed with nitrogen, diluted with DCM, filtered through celite, rinsing with DCM. The filtrate was concentrated in vacuo to give methyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propanoate as a white solid. MS (ESI) m/z; calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:15].O>CN(C=O)C>[Cl:15][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1ccc(C(F)(F)F)nc1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of Example 85B (2.8 g, 15.8 mmol) in 20 mL of anhydrous DMF was added POCl3 (5 mL) at 0° C. The resulting mixture was warmed to room temperature and stirred overnight. The solution was poured into 20 mL of icy water. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=20:1) to afford the title compound (2.1 g, 68.2%). LC-MS: m/z 300 (M+H). 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.72 (s, J=8.0 Hz, 1H), 4.66 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:32](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:32][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNC5CCN(C)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNC5CCN(C)CC5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 81.3 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](1-methylpiperid-4-yl)amine is prepared as described in Example 179a starting with 0.07 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](1-methylpiperid-4-yl)amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.48 cm3 of 5N potassium hydroxide. 0.042 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](1-methylpiperid-4-yl)amine is obtained, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[P:29](Cl)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>O1CCCC1>[C:9]1([P:8]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[P:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Reactant: CCOP(Cl)OCC
Solvent: C1CCOC1
Product: CCOP(OCC)c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Into a four-neck flask was weighed 10.00 g (22.7 mmol) of (2-bromophenyl)[di(1-naphthyl)]phosphine (6). The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 100 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 14.8 mL (23.8 mmol) of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was cooled to −78° C. and thereto was added dropwise a 10 mL THF solution of 3.92 g (23.8 mmol) of diethyl chlorophosphite (manufactured by Aldrich) over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 15 hours. After the completion of the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate={fraction (4/1)}) to obtain the title compound (8.83 g, a pale yellow solid). Yield 81.0%.
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])(C)[Cl:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C=CCCC=C.C[SiH](Cl)[Cl:19]>[Pt]>[CH2:1]([Si:7]([CH3:10])([Cl:8])[Cl:19])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C[SiH](Cl)Cl
Reactant: C=CCCCC[Si](C)(C)Cl
Agent: [Pt]
Agent: C=CCCC=C
Product: C=CCCCC[Si](C)(Cl)Cl
Yield: 68 %

Procedure:
Procedure is similar to the one described above for 5-hexenyldimethylchlorosilane. 8.4 g (100 mmole) of 1,5-Hexadiene was refluxed with platinum catalyst (100ppm). To the mixture 5.7 g (50 mmole) of methyldichlorosilane was added dropwise over 30 min. period. The completion of the reaction was monitored by infrared spectroscopy. The product distilling at 65° C./0.22 mm was obtained in 68% yield.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:52][CH2:53][C@@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>ClCCl.C(OCC)(=O)C.[Cl-].[NH4+]>[OH:60][C@@H:55]1[CH2:56][CH2:57][CH2:58][CH2:59][C@H:54]1[CH2:53][NH:52][C:10]([C:9]1[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][C:8]=1[CH3:13])=[O:12]
Reactant: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)O
Reactant: NC[C@@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NC[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example X1) (0.20 g, 0.76 mmol) in dichloromethane (15 ml) are added N-ethyl-diisopropylamine (0.32 ml, 0.89 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.17 g, 0.91 mmol), and 1-hydroxybenzotriazole hydrate (0.02 g, 0.15 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0° C., before (1R,2S)-2-(aminomethyl)cyclohexanol (0.09 g, 0.76 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield N-[[(1S,2R)-2-hydroxy-cyclohexyl]-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X7) (0.18 g, 0.48 mmol, 63%). [M+H]+376.3.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:1]([CH3:3])[CH3:2])[C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: CC(C)Br
Solvent: O
Product: COc1ccc(C(C#N)C(C)C)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a stirred suspension of sodium hydroxide pels (320.0 g; 8.0 mol) in isopropyl bromide (492.0 g; 4.0 mol) is added 4-methoxyphenylacetonitrile (294.3 g; 2.0 mol) over a 30-minute period at a temperature of 50°-55° C. Following this addition the reaction mixture is stirred at reflux (68°-74° C.) for 4 hours. It is then cooled to 50° C. and water (498 ml) is added. The mixture is subsequently stirred for 15 minutes with cooling. The aqueous and organic phases are then separated and the excess isopropyl bromide is removed from the organic phase by distillation. The resulting product (367.88 g of 2-(4-methoxyphenyl)-3-methylbutyronitrile) is 96.9% pure and corresponds to a real yield of 99.1%. The results of this experiment are included in Table Ia under No. 7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=1[NH2:20]>>[NH2:20][C:12]1[CH:13]=[C:14]([C:15]2[O:17][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:19][C:11]=1[O:10][CH3:9]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: Nc1ccccc1O
Product: COc1ccc(-c2nc3ccccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-aminophenol (326 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 97 mg (13%). 1H NMR (CDCl3) δ 7.66–7.45(m, 4H), 7.24(m, 2H), 6.82(d, J=8.3 Hz, 1H), 3.86(s, 3H). MS 241 m/z (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])[CH2:11][C:10]([CH3:22])([CH3:21])[C:9]=2/[CH:23]=[CH:24]/[C@@H:25]2[O:30][C:29](=[O:31])[CH2:28][C@@H:27]([O:32][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:26]2)=[CH:4][C:3]=1[CH3:50].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[C:15](=[O:20])[CH2:16][CH2:17][C:18]3=[O:19])[CH2:11][C:10]([CH3:21])([CH3:22])[C:9]=2/[CH:23]=[CH:24]/[C@@H:25]2[O:30][C:29](=[O:31])[CH2:28][C@@H:27]([OH:32])[CH2:26]2)=[CH:4][C:3]=1[CH3:50]
Reactant: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC(=O)O3)C(C)(C)CC(N3C(=O)CCC3=O)C2)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC(N3C(=O)CCC3=O)C2)ccc1F
Yield: 597.6 %

Procedure:
In a manner similar to scheme V, 42 (0.13 gm) was treated with tetrabutylammonium fluoride and the product was purified by SiO2 with 1.5:1 EtOAc:hexanes as the eluent. Concentration in vacuo of the product rich fractions provided 0.51 gm of the product. mp 71°-77° C. Anal. C26H30FNO5 500 0.25 H2 0: Theory C: 67.89; H: 6.68; N: 3.04. Found C: 67.83; H: 6.95; N: 2.90.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[CH:25]=CC=[CH:22][CH:21]=1.[OH-].[K+]>CCO>[Cl:12][C:7]1[CH:6]=[C:5]([NH:4][C:1]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:2]=2)[CH:10]=[C:9]([Cl:11])[CH:8]=1
Reactant: Brc1ccccc1
Reactant: CC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Clc1cc(Cl)cc(Nc2ccccc2)c1
Temperature: 175 °C
Yield: 71.4 %

Procedure:
A mixture of 12 g (58.8 mmole) of N-acetyl-3,5-dichloroaniline, 8.13 g (58.8 mmole) of potassium carbonate (dried at 155° C. under vacuum), 23 g (147 mmole) of bromobenzene (dried over molecular sieves), and 1.12 g (5.9 mmole) of cuprous iodide was heated in a 175° C. oil bath under a reflux condenser under nitrogen for 18 hours. The mixture was cooled to room temperature and triturated with 1 liter of benzene. The solution was concentrated in vacuo. The residue was treated with 50 mL of EtOH and 7.76 g (118 mmole) of potassium hydroxide and the resulting mixture was heated to reflux for two hours. The mixture was cooled and the solvent removed in vacuo. The residue was taken up in 150 mL of hexanes and 20 mL of EtOAc and the resulting solution was washed with 2×100 mL of 2N aqueous HCl and 70 mL of water. The latter wash was back extracted with 60 mL of ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 200 g of silica gel with 2 liters of 50:1 hexanes:ethyl acetate to give 10 g (71%) of a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1.CC1C=CC(S(O[CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])(=O)=O)=CC=1.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[C:5]([CH3:11])=[CH:6][C:7]([O:10][CH2:23][CH2:24][C:25]([CH3:27])([OH:28])[CH3:26])=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1cc(O)ncc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(C)(C)O)ncc1Br
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a suspension of sodium hydride (to which about 40% of a mineral oil was added, 0.23 g) in N,N-dimethylformamide (10 mL), 5-bromo-2-hydroxy-4-methylpyridine (1.00 g) was added under ice-cooling and the resultant reaction mixture was stirred for 30 minutes. To the reaction mixture, 3-hydroxy-3-methylbutyl 4-methylbenzene sulfonate (1.51 g) was added and the resultant reaction mixture was stirred at 60° C. for 4 hours. To the reaction mixture, a saturated ammonium chloride aqueous solution was added and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=50:50 to 33:67) to obtain the subject compound (0.92 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH:21]=[CH2:22])[CH2:16][CH:15]=3)[S:13][C:6]=12.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH2:22][NH:35][CH2:34][CH2:33][O:32][CH3:31])[CH2:16][CH:15]=3)[S:13][C:6]=12
Reactant: C=CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Reactant: COCCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCNCCC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Yield: 44.5 %

Procedure:
A solution of the compound 98 (171.0 mg, 0.4 mmol) and 2-methoxyethanamine (0.14 mL, 1.62 mmol) in THF (98.1 mL) was stirred overnight at room temperature. It was then diluted with DCM, washed with aqueous sodium bicarbonate and water. The organic phase was extracted with 1N HCl, the aqueous acidic phase was basified by addition of 1N NaOH (pH ˜11) and extracted with DCM. The DCM extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure affording title compound 99 (89.0 mg, 45% yield) as cream foam. MS (m/z): 501.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[NH:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:23]([C:8]([NH:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=3[Cl:20])=[C:7]([C:21]#[N:22])[CH:6]=[N:5]2)=[CH:24][C:25]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1Br
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A suspension of 3-bromo-4-ethoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (630 mg, 1.29 mmol) in 35 mL of acetonitrile was heated to reflux and phosphorous oxychloride (0.80 mL) was added dropwise, via syringe. The reaction mixture was heated at reflux overnight, then cooled to room temperature. The solids were collected by filtration, washed with saturated aqueous sodium bicarbonate. The solids were stirred with saturated aqueous sodium bicarbonate for 1 hour and then collected by filtration, washed with saturated aqueous sodium bicarbonate and water. The solid was recrystallized from methanol and dried in vacuo to provide 225 mg of 7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-3-quinolinecarbonitrile as a yellow solid, mp >250° C. 1H NMR (400 MHz, DMSO-d6) δ 1.47 (t, J=7 Hz, 3H), 3.87 (s, 3H), 4.32 (q, J=7 Hz, 2H), 7.45 (s, 1H), 7.82 (s, 1H), 8.16(s, 1H), 8.27 (s, 1H), 8.76 (s, 1H), 10.73 (s, 1H); MS (ES) m/z 466.1, 468.0, 470.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[C:5](/[CH3:30])=[CH:6]/[C@H:7]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]>C(O)C.[Pt]>[CH2:1]([O:3][C:4](=[O:31])[C@@H:5]([CH3:30])[CH2:6][CH:7]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Next, to a solution of (E)-(R)-4-tert-butoxycarbonylamino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pent-2-enoic acid ethyl ester (2.5 g, 5.63 mmol) in ethanol (20 mL) is added Pt/C (250 mg) and the mixture is stirred overnight under an atmosphere of hydrogen (H2 balloon). The catalyst is filtered through a Celite pad and, the filtrate is concentrated to give (S)-4-tert-butoxycarbonylamino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](Br)=[C:12]2[CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([CH3:39])[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C(O)C.C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:35]1[CH:36]=[C:37]([CH3:39])[CH:38]=[C:33]([CH3:32])[CH:34]=1)=[C:12]2[CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccc(OCc3ccccc3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(OCc4ccccc4)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[2-(5-benzyloxy-2-bromo-1H-indol-3-yl)ethyl]isoindole-1,3-dione (500 mg in a mixture of 6 mL ethanol and 16 mL toluene) was added 3,5-dimethylphenyl boronic acid (205 mg) followed by 2.7 mL of 1M sodium carbonate. To the stirred solution was added lithium chloride (156 mg) followed by tetrakis(triphenylphosphine)palladium (78 mg) and the mixture heated to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:methylene chloride:ethyl acetate, 15:8:1 then 12:8:1) gave the title compound (479 mg).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:11]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].[OH2:22].NN>C(O)C.[Ni]>[C:1]([NH:5][CH2:6][CH:7]([OH:21])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=1[C:19]([NH2:20])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1cccc([N+](=O)[O-])c1C#N
Reactant: O
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1cccc(N)c1C(N)=O

Procedure:
12.2 g of 1-tert.-butylamino-3-(2-cyano-3-nitrophenoxy)-2-propanol are reacted in 200 ml of ethanol with 11 g of hydrazine hydrate and Raney nickel, analogously to Example 4(d), and after filtering and evaporating the filtrate, this gives crude 6-(3-tert.-butylamino-2-hydroxy-propoxy)-anthranilamide in the form of an oil which is used further without further purification.
Reaction SMILES: [Cl:1][C:2]([Cl:37])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:31])[NH:21][C:22]3[C:27]([CH3:28])=[CH:26][C:25]([Br:29])=[CH:24][C:23]=3[CH3:30])=[CH:16][C:15]=2[N+:32]([O-])=O)=[CH:9][CH:8]=1.[NH4+].[Cl-]>[Fe]>[Cl:36][C:2]([Cl:1])([Cl:37])[CH2:3][O:4][C:5](=[O:35])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:31])[NH:21][C:22]3[C:27]([CH3:28])=[CH:26][C:25]([Br:29])=[CH:24][C:23]=3[CH3:30])=[CH:16][C:15]=2[NH2:32])=[CH:9][CH:8]=1
Reactant: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c(N)c1
Yield: 62.4 %

Procedure:
The product from Example 207A (0.6197 mmol) was reduced with Fe and NH4Cl following the procedure from Example 9E to yield the title compound (239 mg, 62% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:20]1[CH:36]=[C:24]2[N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:17][O:18][C:20]1[CH:36]=[C:24]2[NH:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1
Reactant: OCc1cc(F)c(Oc2cccc(F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Product: O=c1nc(OCc2cc(F)c(Oc3cccc(F)c3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (3,5-difluoro-4-(3-fluorophenoxyl)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.