Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(F)C=CC=1N.CC([O-])(C)C.[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:24])=[CH:19][CH:18]=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[OH:24])=[CH:21][CH:22]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: OC(c1ccc(Br)cc1)c1ccccc1Cl
Yield: 51.7 %

Procedure:
2,4-Difluoroaniline (0.28 ml; 2.7 mmol), NaOtBu (260 mg; 2.7 mmol), Pd(OAc)2 (10 mg; 0.04 mmol), R-(+)-BINAP (10 mg; 0.02 mmol) and (4-bromo-phenyl)-(2-chloro-phenyl)-methanone (200 mg; 0.67 mmol) are dissolved in dioxan (3 ml) and refluxed for 20 min. The reaction mixture is poured on water and extracted with TBME twice. The combined organic phases are dried over Na2SO4, evaporated to dryness and purified via chromatography (SiO2; TBME/hexanes 5/95>2/8) to yield the title compound (103 mg; 44%) as brownish crystals. Recrystallisation from acetone hexanes yields colorless crystals (48 mg; 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[C:23]1([C@@H:29]([NH2:32])[CH2:30][CH3:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:32][C@H:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](N)c1ccccc1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Product: CC[C@H](Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1)c1ccccc1
Temperature: 185 °C
Yield: 40.4 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.15 g, 0.47 mmol) was reacted with (s)-(−)-1-phenylpropylamine (2.0 mL, 1.86 g, 13.8 mmol) in a sealed vial heated in a microwave reactor at 185° C. for 90 min. The crude product was purified by preparative HPLC and lyophilized to give a fluffy, yellow solid (82 mg, 40.4% yield): 1H NMR (400 MHz, MeOD) δ ppm 0.99 (t, J=7.45 Hz, 3 H) 1.78-2.01 (m, 2 H) 4.58 (t, J=7.20 Hz, 1 H) 6.72 (s, 1 H) 7.14-7.37 (m, 7 H) 7.40 (dd, J=2.53 Hz, 1 H) 8.22 (s, 1 H) 8.81 (s, 1 H); HRMS (ESI+) calcd for C24H19ClFN5 432.13858; found (MH+) 432.1391.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[C:14]([N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:30]=1)[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)CN=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of potassium bis(trimethylsilyl)amide (11.34 g, 54 mmol) in THF (100 ml) was added dropwise to a mixture of (benzylidene-amino)-acetic acid methyl ester (3.83 g, 21.63 mmol) and 4-chloromethyl-1-trityl-1H-imidazole (21.6 g, 60.18 mmol) in THF (200 ml) at -78° C. The resulting solution was warmed to ambient temperature and stirred for 24 hours. After removal of THF, the reaction mixture was subsequently partitioned between ethyl acetate and brine. The aqueous layer was washed two times with ethyl acetate. The ethyl acetate extracts were combined, dried over MgSO4, filtered and concentrated to give the crude title compound of example 1A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([N:41]4[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]4)[CH:36]=3)=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3ccnc(N4CCNCC4)c3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 67.1 %

Procedure:
To a 5 mL microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 31 mg, 0.073 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (21.13 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (10 ml) and acidified with 1N HCl. The mixture was then extracted with ethyl acetate (2×50 mL) and the organic layers combined, dried over magnesium sulfate, filtered, and solvents removed by rotary evaporation. The mixture of products, by tlc, was purified by HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA)). However, the product was not there but found in the aqueous extract, 100% clean, which was evaporated to afford the title compound N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({4-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (26 mg, 0.049 mmol, 66.7% yield) as a tfa salt. 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 10.18 (t, J=5.81 Hz, 1H), 8.80 (br. s., 2H), 8.21 (d, J=5.56 Hz, 1H), 7.78 (d, J=8.34 Hz, 2H), 7.43 (d, J=8.34 Hz, 2H), 7.23 (s, 1H), 7.09 (dd, J=5.31, 1.01 Hz, 1H), 5.32 (s, 2H), 4.11 (d, J=5.81 Hz, 2H), 3.76-3.87 (m, 4H), 3.13-3.29 (m, 5H), 1.22 (d, J=7.07 Hz, 6H). MS (ES+) m/e 507 [M+H]+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][C:12](=O)[CH2:13][CH2:14][CH3:15].[BH4-].[Na+]>>[CH3:11][CH:12]([NH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Product: CCCC(C)Nc1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (399 mg; 3 mmol; 1 eq.), 2-pentanal (284 mg; 0.351 ml; 3.3 mmol; 1.1 eq) and NaBH4 (228 mg; 6 mmol; 2 eq.) as described in method 3; Yield: 0.264 g (43.3%); MS m/z: 204.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.88 (t, 3H, 3J=7.5 Hz); 1.10 (d, 3H, 3J=6.2 Hz); 1.32-1.42 (m, 3H); 1.49-1.56 (m, 1H); 3.35-3.37 (m, 1H); 5.02 (br s, 1H); 6.52-6.55 (m, 2H); 7.25 (d, 1H, 3J=8.7 Hz); 7.83 (s, 1H); 11.81 (br s, 1H); HPLC (METHOD [A]): rt 7.79 min (80.5%)
Reaction SMILES: [Cl-].C(C[P+](C)(C)C)#N.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:19]1([CH:25](O)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F:28][C:29]1([F:57])[CH2:34][CH2:33][N:32]([C:35]([C:37]2[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][C:42]([C:46]([N:48]2[CH2:53][CH2:52][N:51]([CH:54]([CH3:56])[CH3:55])[CH2:50][CH2:49]2)=[O:47])=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:57][C:29]1([F:28])[CH2:34][CH2:33][N:32]([C:35]([C:37]2[N:38]([CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:26])[C:39]3[C:44]([CH:45]=2)=[CH:43][C:42]([C:46]([N:48]2[CH2:49][CH2:50][N:51]([CH:54]([CH3:55])[CH3:56])[CH2:52][CH2:53]2)=[O:47])=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH2:30]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(O)c1ccccc1
Agent: C[P+](C)(C)CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)c2ccccc2)CC1

Procedure:
The title compound was synthesized in analogy to example 74, from (cyanomethyl)trimethylphosphonium chloride (prepared according to Tetrahedron Lett. 1996, 37 (14), 2459-62), potassium bis(trimethylsilyl)amide, 1-phenylethanol and (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32) in toluene, to give the compound as a light brown foam (37%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH2:23]1.C[C@H]1COCCN1C1C=C(CS(C)(=O)=O)N=C(N2CCC(N)CC2)N=1>>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:21])[CH3:16])[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(Cl)n1
Agent: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(N)CC2)n1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(N2CCC(N)CC2)n1

Procedure:
1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]piperidin-4-amine was prepared from (3S)-4-{2-Chloro-6-[1-methyl-1-(methylsulfonyl)ethyl]pyrimidin-4-yl}-3-methylmorpholine and tert-butyl N-(4-piperidyl)carbamate in an analogous two step procedure to 1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]piperidin-4-amine.
Reaction SMILES: Cl[CH2:2][C:3]([O-:5])=[O:4].[Li+].[C:7]([O-:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li+]>CN(C=O)C>[C:7]([O:15][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])c1ccccc1
Reactant: O=C([O-])CCl
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(O)COC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
13 g lithium chloroacetate (0.10 m) and 17.6 g lithium benzoate (0.10 m) were combined in a 250 ml R.b. flask with 50 ml DMF. This was heated on an oil bath to 110°-120° C. with magnetic stirring for 3 hrs. (The solution at first was clear, but after 2-3 hrs. a white precipitate formed).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:10]O)[C:4]=2[CH:3]=[CH:2]1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.CCCCCCC=CCCC>O1CCCC1>[N:26]([CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[N+:27]=[N-:28]
Reactant: OCc1cccc2[nH]ccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCCC=CCCCCCC
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cccc2[nH]ccc12
Reaction time: 5 h
Yield: 1810.1 %

Procedure:
To a solution of 1H-indole-4-methanol (71 mg, 0.48 mmol) in tetrahydrofuran (1 mL) at 0° C. was added diphenylphosphoryl azide (156 μL, 0.72 mmol) followed by 1,8-diaza[5.4.0]undec-7-ene (87.4 μL, 0.58 mmol). The cooling bath was removed and the solution was allowed to stir for 5 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 1 M HCl and brine, dried (MgSO4), filtered, concentrated and chromatographed (12% ethyl acetate/hexanes) to give 4-(azidomethyl)-1H-indole (1.496 g, 88%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:26][CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[CH3:22])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(NCCC(C)(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 86.4 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and 3,3-dimethylbutylamine (0.21 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give light yellow solid (0.54 g, 87%): GCMS ml/z 405.00 (M+). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 7.08 (s, 1H), 6.22 (s, 1H), 5.64 (q, 1H, J=7.0 Hz), 4.26 (m, 2H), 3.16 (m, 2H), 1.57 (m, 2H), 1.33 (m, 3H), 0.98 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:8])([O-:3])=[O:2].[F:23][C:24]([F:51])([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][C:47]([F:50])([F:49])[F:48])=[CH:39][CH:38]=1)[O:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](O)=[O:35])=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]1[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:51])[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][C:47]([F:50])([F:49])[F:48])=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=C(OCCCCCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
3.68 g (11.8 mmol) of 6-hydroxyhexyl 3,5-dinitrobenzoate, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) is added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yielded 6.85 g of 6-[((2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate as yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:4]([CH:9]=[C:10]([C:13]#[C:14][Si](C)(C)C)[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[OH:27]S(O)(=O)=O>CC(C)=O>[C:13]([C:10]1[C:11]([F:12])=[C:2]([F:1])[C:3]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:27])[CH3:14]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a suspension of methyl 3,4-difluoro-2-(2-fluorophenylamino)-5-((trimethylsilyl)ethynyl)benzoate (1.20 g, 3.18 mmol) in 85% aqueous acetone (40 ml) were added HgSO4 (943 mg, 3.18 mmol) and H2SO4 (0.33 ml, 6.36 mmol). The reaction was heated at reflux for 24 h. The mixture was cooled to room temperature, concentrated, and diluted with EtOAc (100 ml). The organic solution was washed with H2O (50 ml), dried over Na2SO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=10:90) yielded 832 mg (81%) of methyl 5-acetyl-3,4-difluoro-2-(2-fluorophenylamino)benzoate as a white solid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:18][N:19]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:20][CH:21]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[O:22][CH2:23][CH2:24][O:25]C1CCCCO1>CO>[CH3:18][N:19]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:20][CH:21]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[O:22][CH2:23][CH2:24][OH:25]
Reactant: CN(CC(OCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CN(CC(OCCO)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Yield: 100.9 %

Procedure:
0.56 g of pyridinium paratoluenesulfonate is added to a solution of 10 g of the compound obtained in EXAMPLE 8, step C), in 100 ml of MeOH and the reaction mixture is refluxed for 1 hour 15 minutes. It is concentrated under vacuum and the residue is taken up with ether, washed with water and with a buffer solution of pH 2, dried over MgSO4 and concentrated under vacuum to give 8.2 g of the expected product, which is used as such in the next step.
Reaction SMILES: C(O)(C)C.[O:5]([CH3:7])[Na].[CH3:8][C:9]1[C:14](C)=[CH:13][CH:12]=[C:11]([CH3:16])[C:10]=1[OH:17].C(OO)(C)(C)C>CO.O>[CH3:13][C:14]1[C:7](=[O:5])[CH:12]=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: CO[Na]
Agent: CC(C)(C)OO
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Yield: 99.7 %

Procedure:
10 g of HCL gas were passed into 400 ml of isopropanol at room temperature, 4 g (0.028 mole) of Cu2O were added to the resulting solution, the mixture was heated at 70° C. and 75 liters/hour of air were passed in for 4 hours. Thereafter, 24 ml of a 30% strength solution of NaOCH3 in CH3OH were added at room temperature (a sample has a pH of 4.2 after water had been added), followed by the addition of 28 g (0.2 mole) of 2,3,6-trimethylphenol, the mixture was heated at 40° C. and 18 g (0.2 mole) of tert.-butyl hydroperoxide were then added in the course of 2 hours. At the same time, 75 liters/hour of air were passed into the reaction mixture. After a reaction time of 12 hours, the mixture was worked up as described in Example 1 to give 22.54 g of 99.7% pure 2,3,5-trimethyl-p-benzoquinone. The yield was thus 76% of theory.
Reaction SMILES: [NH+]1C=CC=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Br:18][C:19]1[CH:20]=[C:21]([CH2:27][OH:28])[CH:22]=[C:23]([Br:26])[C:24]=1[Cl:25]>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:23]([Br:26])[C:24]=1[Cl:25])[CH:27]=[O:28]
Reactant: OCc1cc(Br)c(Cl)c(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Br)c(Cl)c(Br)c1
Reaction time: 8 h

Procedure:
Pyridinium chlorochormate (PCC, 3.44 g, 15.9 mmol) was added in one portion to a stirred solution of (3,5-dibromo-4-chlorophenyl)methanol (3.2 g, 11.0 mmol) in CHCl3 (40 mL) at ambient temperature and the reaction mixture was stirred—overnight. The reaction mixture was filtered through Celite®, the Celite® pad was washed with CHCl3 and the filtrate was concentrated to afford the title compound as an off white solid (2.0 g, 62%): mp 110-113° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.27 (s, 2H); ESIMS m/z 297.0 ([M]+).
Reaction SMILES: [I:1]C1C=CC2C3CCN(C(OC(C)(C)C)=O)CC3OC=2C=1.CC1(C)C(C)(C)OB([C:30]2[C:35]3[O:36][CH:37]4[CH:42]([C:34]=3[CH:33]=[CH:32][CH:31]=2)[CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]4)O1>>[I:1][C:30]1[C:35]2[O:36][CH:37]3[CH:42]([C:34]=2[CH:33]=[CH:32][CH:31]=1)[CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]3
Reactant: CC(C)(C)OC(=O)N1CCC2c3cccc(B4OC(C)(C)C(C)(C)O4)c3OC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Product: CC(C)(C)OC(=O)N1CCC2c3cccc(I)c3OC2C1

Procedure:
Tert-butyl 8-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P01 starting from tert-butyl 8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 402 [M+H]+
Reaction SMILES: Cl.[C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=O)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[CH2:14]([C:20](=[CH:23]OCC)[CH:21]=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C[O-].[Na+].C(C1C=CN=C(C2C=CC(C(N)=O)=CC=2)N=1)CCCCC>CCOCC.CO>[CH2:14]([C:20]1[CH:21]=[N:3][C:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]#[N:11])=[CH:7][CH:6]=2)=[N:4][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: CCCCCCC(C=O)=COCC
Agent: CCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
0.082 mol. of 4-amidino-benzoic acid amide hydrochloride, suspended in a solution of 0.082 mol. of 2-n-hexyl-3-ethoxy-acrolein and 0.14 mol. of sodium methylate in 150 ml. of methanol, are stirred overnight under an atmosphere of nitrogen at room temperature. The precipitate obtained by dilution of the mixture with 3 liters of ether is removed by filtration, washed with water until neutral and dried at 40° C. in a vacuum drying cupboard, whereby there are obtained 17.9 g. of 4-(4-n-hexylpyrimid-2-yl)-benzoic acid amide; melting point 231.6°-233.0° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14][OH:15])[NH2:13])=[CH:10][CH:11]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O>[OH:15][NH:14][C:12]([C:9]1[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[NH:13]
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reactant: C1COCCN1
Solvent: O
Product: N=C(NO)c1ccc(NC(=O)CN2CCOCC2)cn1

Procedure:
Compound of example 4 (0.10 g, 0.44 mmol) was stirred in morpholine (1 mL) at 25 ° C. for 2 hours. The reaction mixture was then diluted with water and extracted with chloroform (2×50 mL), followed by extraction with ethyl acetate (2×50 mL). Both organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified using column chromatography (silica gel, 1% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19]2[C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][N:22]=[C:21]([Cl:30])[N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19]2[C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=[C:21]([Cl:30])[N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a solution of ethyl 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (808 mg, 1.86 mmol) in THF (10 mL), aq. 1N NaOH (10 mL, 10.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (745 mg).