Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])(=[O:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[C:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:38][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)[CH:39]=[CH:40][CH:41]=1)(=[O:33])[CH3:32]
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(Nc3cccc4c3ccn4C)n2)c1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (60 mg, 0.15 mmol) in NMP (0.6 mL) was added 3-acetamidoaniline (25 mg, 0.165 mmol) and pTsOH.H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (20 mg). MS found for C22H21N7O2 as (M+H)+ 416.3. λ=211.3, 250.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[O:11]=[C:12]1[NH:20][CH:19]=[N:18][C:17]2[N:16]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH:15]=[N:14][C:13]1=2>C(#N)C>[O:11]=[C:12]1[NH:20][CH:19]=[N:18][C:17]2[N:16]([CH2:21][CH2:22][C:23]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:24])[CH:15]=[N:14][C:13]1=2
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
475 mg (3.29 mmol) of 4-(3-aminopropyl)morpholine was added to a 10 ml round bottom flask equipped with a magnetic stirring bar. The flask was heated to 100°-120° C. and 250 mg (1,06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester AIT-0027 was added to the stirring flask. Heating was continued for two hours. The solution was allowed to cool to room temperature and was then treated with 8 ml acetonitrile with stirring. A white precipitate formed and the solution was filtered after 20 minutes of stirring in acetonitrile. The filtrate was washed with acetonitrile and then with ether. This yielded 130 mg of a white solid. The mother liquor was allowed to stand overnight in a fume hood and was filtered the next day to yield another 100 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(4-morpholinyl)propyl]propanamide (AIT-0043). Yield: 65%. m.p. 145°-148° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)([CH2:16][CH2:17][C:18]([O:20]C)=O)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:8].CCOC(C)=O.CCCCCCC>C1(C)C=CC=CC=1>[C:7]([C:9]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:18](=[O:20])[CH2:17][CH2:16]1)#[N:8]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)C1CC(C#N)(c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a 12-L, three-neck flask equipped with a temperature probe, reflux condenser, addition funnel and overhead stirrer was charged with potassium tert-butoxide (266 g, 2.3 mol) and toluene (1 L). A solution of dimethyl 4-cyano-4-(3,4-dichlorophenyl)-heptanedioate (402 g, crude, 386 g theoretical, 1.07 mol) in toluene (3 L) was added through an addition funnel. The reaction mixture was heated to 90° C. and stirred for 1 h. The progress of the reaction was monitored by TLC (4:6 EtOAc/Heptane; stained using Hanessian solution). After 1 h, the reaction mixture was cooled to 15° C. and quenched slowly with 2 M HCl (2.3 L). The phases were separated and the aqueous phase was extracted with MTBE (1 L). The combined organic phases were washed with brine (2×1 L), dried over MgSO4, filtered and concentrated under reduced pressure at 40-45° C. to yield the title compound (424 g, >100%) as a yellow solid. The crude was taken into next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]4[CH:38]=[CH:37][C:28]5[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=5[CH:26]=4)[CH:18]=3)=[C:12]([CH3:39])[CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:39])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]4[CH:38]=[CH:37][C:28]5[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=5[CH:26]=4)[CH:18]=3)=[C:14]([CH3:16])[CH:15]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCN(C(C)=O)C5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1CC[C@H](Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)O)c3)c(C)c2)C1
Reaction time: 3 h
Yield: 48.5 %

Procedure:
The crude methyl 2-((S)-6-((4′-(((S)-1-acetylpyrrolidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 9a (40 mg, 0.08 mmol) was dissolved in 2 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (0.4 mL, 0.40 mmol). The reaction solution was stirred for 3 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((4′-(((S)-1-acetylpyrrolidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 9 (20 mg, yield 51.3%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].O>C(#N)C>[C:32]([O:31][C:29]([C:28]1[CH:27]=[C:26]([CH:38]=[CH:37][CH:36]=1)[CH2:25][NH:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(CN[C@@H](Cc2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of tert-butyl L-phenylalaninate hydrochloride (456 mg) in acetonitrile (8.00 mL) were added potassium carbonate (510 mg) and tert-butyl 3-(bromomethyl)benzoate (400 mg), followed by stirring at room temperature overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[3-(tert-butoxycarbonyl)benzyl]-L-phenylalaninate (340 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:37](=[O:39])[CH3:38])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 41 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (20.6 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.043 ml) and acetyl chloride (0.011 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. To the reaction mixture was added a 1 N aqueous solution of sodium hydroxide (1.5 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.3 mg, 41%) as white powder.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:26][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:21][CH:22]=1
Reactant: O=C(CCc1ccc(F)cc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(F)cc2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 3.1 mL of methyl acetoacetate, 1.2 g of NaH 60% dispersion in oil, 18 mL of 1.6M n-butyl lithium in hexane, 6.0 g of 3-(4-fluorophenyl)propiophenone and 200 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 4 hours. The crude product was triturated from diethyl ether to afford a solid (m.p. 155°-157° C.). 1 H NMR (CDCl3) δ2.23-2.29 (m, 2H), 2.42-2.52 (m, 1H), 2.67-2.78 (m, 1H), 2.97 (dd, 2H), 3.35 (dd, 2H), 7.34-7.47 (m, 5H), 6.91-7.07 (m, 4H).
Reaction SMILES: [Si](OC1C=C2C(=CC=1)CC(C1C=CC(OC)=CC=1N)CC2)(C(C)(C)C)(C)C.Cl.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:33](Cl)=O.[Si:48]([O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][CH:61]([C:66]1[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][C:67]=1[NH:74][CH2:75][C:76]1C=CC(OCCN3CCCCC3)=C(F)C=1)[CH2:60][CH2:59]2)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>>[Si:48]([O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][CH:61]([C:66]1[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][C:67]=1[N:74]([CH2:75][CH3:76])[CH2:33][C:32]1[CH:36]=[CH:37][C:38]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[C:30]([F:29])[CH:31]=1)[CH2:60][CH2:59]2)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O[Si](C)(C)C(C)(C)C)ccc2C1

Procedure:
Synthesized from 2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, {2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (480 mg) was used according to an analogous synthetic method to Example 36 to provide {2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (405 mg). This compound (403 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (293 mg).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][N:9]=1.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+:66].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[Na+:66].[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=1)[CH2:6][N:7]([CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[CH:12][N:13]=1
Reactant: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCC(=O)OC(C)(C)C)cn2)c(-c2cc(C(C)C)ccc2OC)cc1OC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCC(=O)[O-])cn2)c(-c2cc(C(C)C)ccc2OC)cc1OC
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To tert-butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-propionate (41 mg) is added a 4N-hydrochloric acid/dioxane (4 ml) and the mixture is stirred at room temperature for 9 hours. The reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution and the mixture is made weakly acidic with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:3) and the resulting purified product is dissolved in ethanol (0.5 ml) and thereto is added 1M-aqueous sodium hydroxide solution (24 μl) and the mixture is concentrated under reduced pressure to give 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-propionic acid sodium salt (18 mg). MS (m/z): 706 [M−Na]−
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](/[F:15])\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:16]([OH:18])=[O:17].[C:20]([C@@H:22](O)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)#[N:21]>>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](/[F:15])\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[C@H:3]1[C:16]([O:18][C@H:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)=[O:17]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C(/F)C(=O)OCC(F)(F)F
Reactant: N#C[C@@H](O)c1ccc(F)c(Oc2ccccc2)c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C(/F)C(=O)OCC(F)(F)F

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropanecarboxylate melting at 85° C. and having a specific rotation of [α]D20 =+43°±2.5° (c=0.65% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[CH2:4][P:5](=[O:12])([O:9]CC)[O:6]CC.Cl>>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[CH2:4][P:5](=[O:6])([OH:9])[OH:12]
Reactant: CCOP(=O)(Cc1c(Cl)cccc1Cl)OCC
Agent: Cl
Product: O=P(O)(O)Cc1c(Cl)cccc1Cl

Procedure:
O,O-Diethyl 2,6-dichlorobenzylphosphonate (1794 grams) and concentrated hydrochloric acid (2 l) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux for a period of 16 hours. The mixture was then cooled in the formation of a solid product. This product was recovered by filtration was washed with water and dried to yield the desired product 2,6-dichlorobenzylphosphonic acid having a melt point of 211° to 218° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
A mixture of 22.16 g (0.186 mol) of 4-cyanophenol, 32.07 g (0.192 mol) of ethyl bromoacetate, 27.6 g (0.199 mol) of K2CO3 and acetone (250 ml) is stirred at room temperature for 12 hours. After filtration, the solvent is evaporated off under vacuum and the residue is partitioned between an organic phase (ethyl acetate) and an aqueous phase (water). The organic layer is dried (MgSO4) and concentrated under vacuum to give 36.42 g (95%) of ethyl 4-cyanophenoxyacetate (white solid, melting point: 49-50° C.).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([NH2:13])[CH3:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl.O>[CH2:8]([O:7][C:5](=[O:6])[C:4]([NH:13][CH2:11][CH3:12])=[O:10])[CH3:9]
Reactant: CCN
Reactant: CCOC(=O)C(=O)OCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.3 %

Procedure:
To 135,8 ml (1000 mM) of diethyloxalate and 1 g of aliquat 336, in 1000 ml of dichloromethane, were added 64 ml (1000 mM) of ethylamine at 70% in water. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was dried over anhydrous sodium sulfate and the solvent was removed under vacuum to give an oil, which was further purified by silica gel column chromatography, using dichloromethane/dimethylketone (95/5) as eluant, to give 59.9 g of ethyl(ethyl amino)(oxo)acetate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][C@H:26]1[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[O:37])[NH:27]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:27]2[C@@H:26]([CH3:25])[C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [OH:1][CH:2]([CH:7]=[CH2:8])[C:3]([O:5][CH3:6])=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13](S(C)(=O)=O)[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CO>C(C(C)=O)C.C(Cl)(Cl)Cl>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([O:1][C:2](=[CH:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[N:12]=1
Reactant: C=CC(O)C(=O)OC
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCC(C)=O
Solvent: CO
Product: CC=C(Oc1nc(OC)cc(OC)n1)C(=O)OC
Yield: 78.1 %

Procedure:
A mixture of methyl 2-hydroxybut-3-enoate (0.80g, 6.9mmol), 4,6-dimethoxy-2-methanesulphonylpyrimidine (1.50g, 6.9mmol) and potassium carbonate (1.04g, 7.6mmol) in methyl ethyl ketone (100ml) was refluxed for 12 hours. The reaction mixture was filtered and the filtrate evaporated in vacuo. Flash column chromatography (silica, 1.5% methanol in chloroform) of the residue gave the title compound (1.37g, 78% yield by weight).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2)=O.Cl.[NH2:50][OH:51]>N1C=CC=CC=1>[OH:51][N:50]=[CH:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([NH:14][C:15]1[CH:46]=[CH:45][C:18]([C:19]([N:21]([CH3:44])[C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])=[O:20])=[CH:17][C:16]=1[O:47][CH3:48])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: NO
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=O)cc12
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C=NO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 4-[(2-formylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in pyridine (4.0 ml) was added hydroxylamine hydrochloride (21.3 mg), and the solution was stirred at ambient temperature for 1 hour. The resulting solution was concentrated in vacuo and the residue was diluted with chloroform. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrate in vacuo to give 4-[(2-hydroxyiminomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (203 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][NH2:10].Cl[C:13]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]2[NH:22][CH:23]=[CH:24][C:14]=12.[I-].[Na+].CN(C)C=O>CN1CCCC1=O.C(N(CC)CC)C.O>[CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][NH:10][C:13]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]2[NH:22][CH:23]=[CH:24][C:14]=12
Reactant: CC1(C)[C@H]2CC[C@@H](CN)[C@@H]1C2
Reactant: NC(=O)c1cnc2[nH]ccc2c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)[C@H]2CC[C@@H](CNc3c(C(N)=O)cnc4[nH]ccc34)[C@@H]1C2
Temperature: 130 °C
Reaction time: 17 h
Yield: 53.8 %

Procedure:
To 1-[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methaneamine (61 mg) were added a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (39 mg) in 1-methyl-2-pyrrolidone (0.6 ml), triethylamine (0.056 ml), and sodium iodide (3 mg), and the mixture was stirred at 130° C. for 17 hours. After the reaction mixture was left to cool, to the reaction mixture were added N,N-dimethylformamide (0.3 ml) and water (0.1 ml), and the reaction mixture was dissolved. The reaction mixture was directly purified by preparative HPLC (101M-NH4HCO3+NH3 (pH=9.2):CH3CN=98:2 to 30:70). The active fraction was concentrated and dried to hardness to obtain 4-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (33.5 mg) as a solid.