Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].Cl>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CC1CCCCN1CCN
Agent: Cl
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 60 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (+)-2-[2-[(dipropylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 60% of theory. Colourless crystals, m.p. 164°-165° C. (acetonitrile); [α]D20 =+7.24° (dilute aqueous hydrochloric acid).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[F:32])#[N:24].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([C:23]#[N:24])=[C:26]([F:32])[CH:27]=2)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ncnc(Cl)c2OCc2ccccc2)cc1
Reactant: N#Cc1ccc(N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncnc(Nc3ccc(C#N)c(F)c3)c2OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
The compound from step 4 (0.3 g, 0.96 mmol) was dissolved in DMF (4.83 ml), 4-cyano-3-fluoroaniline (0.131 g, 1 eq) and NaH (0.155 g of 60% dispersion in mineral oil, 4 eq) were added. After 1 hour LCMS showed complete conversion, the reaction was quenched with NH4Cl(sat) and extracted with EtOAc. The extracts were dried concentrated and the residue purified by silica gel chromatography (0-20% EtOAc in hexane) to give 0.3 g of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([OH:38])[CH:36]=[CH:37][C:30]=3[OH:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(O)ccc1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1ccc(O)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,5 dihydroxybenzaldehyde. MS (ESI) m/z 501.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH:16]2[CH2:18][CH2:17]2)=[CH:14][C@H:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:27]([O:30][N:31]([C@H:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:15]([CH:16]2[CH2:17][CH2:18]2)=[CH:14]1)[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C=C(C2CC2)[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 238, 2.74 g, 7.14 mmol) and N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 1.85 g, 7.14 mmol) following the procedure described for Intermediate 10. The desired product was obtained as a light yellow oil (3.19 g, 71%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][CH2:12][O:13][C:14]([CH:16]([C:20]([CH3:22])=O)[C:17]([CH3:19])=O)=[O:15]>>[CH2:12]([O:13][C:14]([C:16]1[C:17]([CH3:19])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[C:20]=1[CH3:22])=[O:15])[CH3:11]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2cccc(Cl)c2)c1C
Yield: 58 %

Procedure:
In analogy to the procedure described in Example 38A], 3-chlorophenylhydrazine hydrochloride and ethyl diacetoacetate gave the title compound after purification by flash column chromatography (n-heptane:EtOAc 9:1-1:1) in 58% yield as light yellow solid. MS: 279.0 (MH+, 1 Cl).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH3:12])[CH2:7][CH2:6]1.[F:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23]([Cl:25])=[O:24]>CO>[ClH:25].[ClH:1].[F:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N:11]([CH3:12])[CH:8]2[CH2:7][CH2:6][N:5]([CH3:4])[CH2:10][CH2:9]2)[CH:14]=1)=[O:24]
Reactant: CN1CCC(N(C)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Agent: Cl
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2)CC1
Temperature: 106.5 °C
Yield: 47.6 %

Procedure:
Load 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidine trihydrochloride (Preparation 11, 240 mg, 1.094 mmol) in methanol (2 ml) onto a SCX column (2 g cartridge, Varian). Elute with ammonia (2.0 M in methanol) to obtain the corresponding free base. Concentrate to dryness. Dissolve the resulting brown oil in dioxane (2 mL) and divide the solution into two aliquots (2×1 mL). Take one of the aliquots and add dioxane (1 mL). Add 2,4,6-trifluoro-benzoyl chloride (0.052 mL, 0.401 mmol) neat. Shake and heat at 106.5° C. for 2 hr. Cool to ambient temperature and load onto a SCX column (1 g cartridge, Varian). Elute with ammonia (2.0 M in methanol). Purify further by flash chromatography using 20/1 mixture of dichloromethane and 2.0 M ammonia in methanolto provide the free base of the title compound (86 mg, 62%). Following a salt formation method similar to Example 1 gives the title compound as a white solid (99 mg): mp 199–200° C.; mass spectrum (free base, ion spray): m/z=378.2 (M+1), 1H NMR (free base, CDCl3): 7.44 (bs, N—H), 7.31 (bs, 1H), 7.19 (t, J=8.3 Hz, 1H), 6.80–6.73 (m, 3H), 6.60 (dd, J=2.2 Hz, 8.3 Hz, 1H), 3.64 (tt, J=4.0 Hz, 11.9 Hz, 1H), 3.05 (bd, J=10.8 Hz, 2H), 2.81 (s, 3H), 2.38 (s, 3H), 2.28–2.17 (bm, 2H), 2.06–1.92 (bm, 2H), 1.76 (bd, J=12.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:28])[C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCCC3=O)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCC(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 328.9 %

Procedure:
5,6-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 5b) (0.15 g, 0.036 mmol) was dissolved in dry THF, cooled to −78° C. and LiHMDS (0.8 mL, 0.88 mmol, 1M solution in THF) was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. The reaction mixture was cooled to −78° C. and MeI (0.05 ml, 0.88 mmol) was added slowly, and the reaction mixture was slowly, warmed to room temperature and stirred for 4 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2×50 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material obtained was purified by column chromatography using [EtOAc-hexane (1:9) as eluant] to afford the title compound (0.05 g, 32%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.54 (d, J=9 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 3.55-3.49 (m, 1H), 3.22-3.15 (m, 1H), 2.68-2.64 (m, 1H), 2.42 (s, 3H), 2.27-2.22 (m, 1H), 1.95-1.87 (m, 1H), 1.25-1.17 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[C:10]([CH3:26])([N:11]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([O:18][C:16]([N:11]1[CH2:12][CH2:13][CH:14]2[CH2:15][NH:8][CH2:9][C:10]12[CH3:26])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCN(C(=O)OCc3ccccc3)C2(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC12CNCC1CCN2C(=O)OCc1ccccc1
Yield: 55.4 %

Procedure:
The product of Example 20F (0.8 g, 2.22 mmol) was treated with TFA (5 mL) in CH2Cl2 (10 mL) at ambient temperature for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 90:9:1 CH2Cl2:MeOH:NH4OH) to give the title compound (0.32 g, 1.23 mmol, 55% yield). 1H NMR (MeOH-d4, 300 MHz) δ 1.42, 1.47 (s, 3H, rotamers), 1.63-1.75 (m, 1H), 1.98-2.13 (m, 1H), 2.37-2.52 (m, 1H), 2.62-2.76 (m, 2H), 3.00-3.12 (m, 1H), 3.26, 3.47 (d, J=12.6 Hz, 1H, rotamers), 3.53-3.62 (m, 2H), 5.08, 5.13 (s, 2H, rotamers), 7.25-7.42 (m, 5H); MS (DCl/NH3) m/z 261 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:11][C:12]([O:14]C(C)(C)C)=O)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH:20]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:21](C(O)=O)[CH:22]([CH3:24])[CH3:23].C(OC([C@@]1(NC([C@@H]2C[C@@H](OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)C[C@H]2C(=O)N[C@H](C(=O)N[C@@H](C2CCCCC2)C(=O)NC)C(C)(C)C)=O)C[C@H]1C=C)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:11][C:12](=[O:14])[C@@H:21]([NH:20][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH:22]([CH3:24])[CH3:23])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCCC1
Yield: 94.4 %

Procedure:
Compound 54 (93 mg, 0.343 mmol) was deprotected and coupled to Z-Val-OH (95 mg, 0.378 mmol) according to the method for the preparation of 39. Flash column chromatography (toluene/ethyl acetate 4:1) gave 55 (131 mg, 94%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1OC1C.CCN(CC)CC>CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCCCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (18 g, 0.077 mol) and 1-bromo-7-phenyl heptane [Example 1a] (15 g, 0.059 mol) in HMPA (45 ml) at 130° C., was added, dropwise, during 1 h, a solution of propylene oxide (18 ml) and Et3N (1 ml). After six more hours, second portions of propylene oxide (4 ml) and Et3N (1 ml) were added and heating was continued for 4 h. The cooled mixture was extracted successively with pet ether, Et2O and Me2CO. The residue returned 2.5 g of starting material (i.e., 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline). The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O) dried (Na2SO4) and concentrated to a viscous oil. This material was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. Concentration of the eluates and crystallization of the residue from pet ether (Darco) gave 12 g, (50%) of 6-methoxy-4-methyl-8-nitro-5-(7-phenyl heptoxy) quinoline as yellow crystals, mp 53°-54° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:15])=O.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:15][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: OCCn1cnc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: ClCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a slurry of 30 g (0.185 mole) of 1-(2-hydroxyethyl)benzimidazole in 200 ml of methylene chloride was added dropwise 13.5 ml (0.185 mole) of thionyl chloride in 50 ml of the same solvent. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was added to an equal volume of water and made basic (pH 8-9) by the addition of sodium bicarbonate. The organic phase was separated, dried over magnesium sulfate and evaporated to give 27.3 g of product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:3]=1.[CH:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[CH:18]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=3[F:17])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: Fc1cccc(F)c1COc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cccc(F)c1COc1cc(C2CC2)ccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 500 mg (1.66 mmol) of 4-bromo-2-[(2,6-difluorobenzyl)oxy]pyridine (Example 145A), 365 μl (2.0 mmol) of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 139 mg (0.17 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride-dichloromethane complex and 1.63 g (5.0 mmol) of caesium carbonate in 0.5 ml of water and 4 ml of dioxane was degassed with argon for 5 min and stirred in a sealed tube at 100° C. for 2 h. The reaction mixture was cooled to room temperature and the residue was partitioned between ethyl acetate and water. The organic phase was removed and washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: methanol/ethyl acetate, gradient 0% to 25%). This gave 350 mg of the target compound (80% of theory).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:23])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:24][C:25]([F:36])([F:35])[CH2:26]OS(C(F)(F)F)(=O)=O>C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([CH2:26][C:25]([F:36])([F:35])[F:24])[C:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(CC(F)(F)F)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
To a suspension of 60% sodium hydride (0.678 g, 16.97 mmol) in THF (100 mL) at room temperature was added malonic acid dibenzyl ester (4.825 g, 16.97 mmol) to give a clear solution after 30 min. Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (3.52 g, 15.43 mmol) was added and reaction mixture was stirred at 50° C. for 48 h. The reaction mixture was concentrated, partioned between ethyl ether and washed with saturated ammonium chloride solution and acidified with 1N HCl. The mixture was extracted with ethyl ether (2×), dried (MgSO4), and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 0 to 0% ethyl ether/hexanes) to give a colorless oil (3.844 g, 68%). 1H NMR (300 MHz, CDCl3): δ 7.4-7.2 (m, 10H), 5.15 (s, 4H), 3.75 (t, J=6.9 Hz, 1H), 2.9-7.7 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Triethylamine (17.35 mL, 124 mmol) was added to a solution of 7-bromo-4-chloro-3-nitroquinoline (29.84 g, 104 mmol) in dichloromethane (253 mL), and the reaction was cooled to 0° C. 1-Amino-2-methylpropan-2-ol (10.17 g, 114 mmol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed with water. The crude solid was recrystallized from a mixture of isopropanol and acetonitrile to provide 27.78 g of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:22])[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:22])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: Cc1cc(C#N)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C#N)cc2c1NC(c1cccc(NC3(C(=O)O)CC3)c1)CC2(C)C
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (355.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyano-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (79.8 mg, 21.3%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 376.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]([OH:34])=[O:11]
Reactant: O=P([O-])(O)O
Reactant: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Yield: 98.1 %

Procedure:
To a solution of 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (1.87 g, 4.28 mmol) in acetonitrile (12.0 ml) were added an aqueous solution (7.0 ml) of sodium dihydrogen phosphate (4.01 g, 33.42 mmol), an aqueous solution (7.0 ml) of sodium hypochlorite (1.74 g, 19.33 mmol) and an aqueous hydrogen peroxide (1.89 ml, 30%) and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (1.90 g, 4.20 mmol, 98%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5](O)[C@H:4]([CH2:8][C:9]([OH:11])=[O:10])[C@H:3]1[CH:12]=[CH:13][C@H:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC(OC)(C)C.ClC(Cl)(Cl)C(O)=O>C(N(CC)CC)C>[OH:1][C@H:2]1[CH2:6][C@H:5]2[O:10][C:9](=[O:11])[CH2:8][C@H:4]2[C@@H:3]1/[CH:12]=[CH:13]/[C@H:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC[C@@H](O)C=C[C@@H]1[C@@H](CC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](O)/C=C/[C@H]1[C@@H]2CC(=O)O[C@@H]2C[C@@H]1O

Procedure:
2-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-1-octenyl]cyclopentyl]acetic acid (XIX, EXAMPLE 11, 2.55 g) is stirred with MTBE (100 mL) and trichloroacetic acid (0.102 g). The slurry is heated to reflux for more than one hour. Then triethylamine (0.2 mL) is added. The mixture is cooled and washed once with water (50 mL) of water. The mixture is dried over anhydrous granular sodium sulfate and then concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) δ 5.58, 5.43, 4.88, 4.03, 3.92, 3.55, 2.8, 2.71, 2.3-2.5, 2.22, 1.9, 1.2-1.6 and 0.89; CMR (CDCl3, 100.6 MHz) δ 176.94, 136.79, 130.20, 82.41, 76.27, 72.78, 56.12, 42.34, 39.61, 37.05, 33.98, 31.60, 25.06, 22.52 and 13.94.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>O>[N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2)=[N+:19]=[N-:20]
Reactant: Nc1cc2nc(O)c(O)nc2cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc2nc(O)c(O)nc2cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 757.6 %

Procedure:
A solution of 2 g (9,6 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxaline in 40 ml 50% fluoroborio acid was added 100 ml water, filtered and then ice-cooled. A solution of 0,68 g (9,9 mmol) sodium nitrite in 20 ml water was added, and after stirring at 0° C. for 15 min. 0,68 g (1,0 mmol) sodium azide dissolved in 20 ml water was added. Stirring was continued at 25° C. for 2 h. The precipitate was filtered off and washed with water to give 1,8 g (80%) 6-azido-7-chloro-2,3-dihydroxyquinoxaline. IR (KBr): 2100 cm-1 (N3). NMR (DMSO-d6): 11.7 (2H, broad s), 7.03 (lH,s), 6.93 (lH,s).