Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Clc1ccc(-c2ccccn2)cn1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(-c3ccccn3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-ethylpiperazine and 6′-chloro-[2,3]bipyridinyl.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:33])[N:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:20]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C(OCC)(=O)C.O1CCCC1>[S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:33])[N:17]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:20]=2)=[CH:13][CH:14]=1)(=[O:7])(=[O:8])[NH2:5]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
80 mg of 3-[4-(tert-butylaminosulfonyl)phenyl]-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 3 ml of trifluoroacetic acid, followed by heating under reflux for 1 hour. It was left to cool to room temperature, and then the reaction mixture was diluted with ethyl acetate/tetrahydrofuran, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, and then evaporated. The resulting crude crystals were washed with ethyl acetate, to give 60 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.Cl>C(OCCO)C>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: O
Product: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
5.0 g (32 mmol) of 2-chloro-3-nitropyridine was dissolved in 2-ethoxyethanol (150 mL), and water (150 mL) was added thereto. To the mixed solution, 3.9 g (32 mmol) of 4-methoxyaniline and 6 N hydrochloric acid (1 mL) were added, and the mixture was heated to reflux for 12 hours while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure, to obtain 6.6 g (yield: 85%) of N-(4-methoxyphenyl)-3-nitropyridin-2-amine as orange-colored crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:6]([OH:8])=O)#[N:2].[NH2:19][C:20]1[C:21]([F:28])=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26].C([O-])(O)=O.[Na+]>O=S(Cl)Cl.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:6]([NH:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([OH:27])[C:21]=1[F:28])=[O:8])#[N:2]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: N#Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)Nc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
3-Cyano-5-(3-fluorophenyl)benzoic acid (500 mg, 2.1 mmol, 1 eq) was dissolved in SOCl2 (15 mL) and heated at reflux overnight. The excess SOCl2 was removed under reduced pressure and the residue that remained dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-difluorophenol (280 mg, 2 mmol, 0.95 eq) and NaHCO3 (880 mg, 10.5 mmol, 5 eq) in THF (40 mL). The reaction was stirred at room temperature for 3 h, then filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a white solid (500 mg, 64%).
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][CH:8]=1.[H][H]>O1CCOCC1.[Pd]>[OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([OH:22])[CH:16]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(O)CCCCc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)(O)CCCCc1ccc(CCc2cc(O)cc(O)c2)cc1

Procedure:
414 mg (1.27 mmol) of 5-{2-[4-(5-hydroxy-5-methylhexyl)phenyl]vinyl}benzene-1,3-diol in 40 ml of dioxane and 42 mg of 10% palladium/carbon are placed in a reactor. A hydrogen pressure of 7 bar is exerted for 4 hours at room temperature. The reaction medium is filtered on celite and the filtrate is evaporated. The product is crystallized from an ethyl acetate/hexane mixture.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:25][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: ClCC1CO1
Reactant: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2cc(-c3ccccc3)c(C)s2)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (300 mg, 0.86 mmol) in 2-propanol (7.5 mL) and 3 N aq. NaOH (2.5 mL) is treated with epichlorohydrine (158 mg, 1.72 mmol) and the mixture is stirred at rt for 24 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated and the residue is purified by CC on silica gel eluting with hepaten:EA 5:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(5-methyl-4-phenyl-thiophen-2-yl)-propan-1-one (92 mg) as an oil; LC-MS: tR=1.13 min, [M+1]+=407.24.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1>>[O:21]([C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:2]3[S:1][CH2:6][CH2:5][S:4][CH:3]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Reactant: O=C(O)C1=CSCCS1
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)C1=CSCCS1
Yield: 78.4 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5,6-dihydro-1,4-dithiin-2-carboxylic acid (10.9 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (11.9 g), and heating for 18 hours under reflux. The product obtained, after precipitation in water, washing with water and drying (18 g; m.p. approximately 240° C.), is purified by recrystallization in dimethylformamide (150 cc). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-5,6-dihydro-1,4-dithiin-2carboxamide (15 g), m.p. 245° C., is thereby obtained.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13]>>[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH:17][C:8]([C:7]1[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=1[CH:1]=[O:2])=[O:10])[CH3:13]
Reactant: CCN(CC)CCN
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Yield: 94.4 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol) reacted with N,N-diethylethylenediamine (3.03 mL, 21.5 mmol) to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (4.65 g, 94%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.[Cl:16]N1C(=O)CCC1=O>CC#N>[Cl:16][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:4]=1[CH:3]([O:2][CH3:1])[O:14][CH3:15])[NH:11][CH2:10][CH2:9][CH2:8]2
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1Cl)CCCN2
Reaction time: 20 h

Procedure:
A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 200 mg, 0.960 mmol) in MeCN (5 ml) was treated with N-chlorosuccinimide (145 mg, 1.086 mmol), stirred for 20 h. The reaction mixture was concentrated; the residue was treated with Et2O and EtOAc, washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product containing fractions were concentrated. The residue was dissolved in EtOAc, washed twice water (2×) and brine, dried over Na2SO4, filtered and concentrated to give the title compound as a pale yellow oil. (UPLC-MS 1) tR 0.68 min; ESI-MS 243.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].Br[CH:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].C(N(CC)CC)C>O1CCCC1>[OH:11][CH2:12][CH2:13][CH:8]1[N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:1])[C:9]1=[O:10]
Reactant: CNCCNC
Reactant: O=C1OCCC1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C)C(CCO)C1=O

Procedure:
The mixture of sym. dimethylethylenediamine (1 eq, 53 g), bromobutyrolactone (1 eq, 100 g) and triethylamine (1 eq, 120 ml) in 1000 mL of tetrahydrofuran was refluxed overnight. The crude precipitate was filtered and thoroughly washed with diethyl ether. The ether was evaporated and the residue was purified by elution through a silica gel column using 2% (v/v) methanol in chloroform to obtain the title compound. A small sample was converted into a picrate and crystallized from methanol to obtain the picrate salt of the title compound: mp 157°-159° C.; IR (KBr) 3220, 1650, 1565 and 1330 cm-1 ; UV max (MeOH) 353 nm (ε 18090); and NMR (DMSO-d6) δ 2.1 (m, 2H), 2.9 and 2.93 (singlets, 6H), 3.5 (m, 6H), 3.95 (m, 1H), and 8.55 (s, 2H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][O:7][CH2:8][C:9](=[O:16])[C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>CCOCC>[CH:1]1([C:9]([OH:16])([C:10]#[C:11][Si:12]([CH3:13])([CH3:15])[CH3:14])[CH2:8][O:7][CH3:6])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: COCC(=O)C#C[Si](C)(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCC(O)(C#C[Si](C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
52.85 ml of 0.5 M cyclopropylmagnesium bromide (26.43 mmol, Aldrich) are added to a solution of 3 g of 1-methoxy-4-(trimethylsilyl)but-3-yn-2-one (17.62 mmol) in 160 ml of ether. The mixture is stirred at ambient temperature overnight and is then cooled with a water/ice bath and a solution of NH4Claq and ethyl acetate is added. The mixture is extracted 3 times with ethyl acetate and the organic phases are then combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The oily residue is purified by silica column chromatography, elution being carried out with a cyclohexane:ethyl acetate gradient, 100:0 to 80:20, so as to obtain 1.9 g of (±)-2-cyclopropyl-1-methoxy-4-(trimethylsilyl)but-3-yn-2-ol in the form of an oil, with a yield of 51%.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:24])=[CH:18][CH:19]=3)[C:14]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=2[CH:12]=1.[OH-].[K+].C(O)C>C(O)C>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:23]=[CH:22][C:21]3[C:20]4[C:15](=[CH:16][C:17]([Br:24])=[CH:18][CH:19]=4)[C:14]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[CH:12]=2)=[C:4]([CH:9]=1)[C:3]([OH:41])=[O:2]
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(-c3ccc(Br)cc3C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(-c3ccc(Br)cc3C(=O)O)cc21
Temperature: 25 °C
Yield: 102.3 %

Procedure:
35 g (51.2 mmol) 16 is suspended in 300 ml ethanol and treated with 50 ml 50% KOH/ethanol solution and heated to reflux for 3 h. After cooling to room temperature with reaction mixture is diluted with 200 ml ethanol, with precipitation is collected by filtration, the residue is washed with ethanol and dried in vacuum. 35 g (yield: 98%) of a white solid can be obtained.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]4)[C:14]3=O)=[CH:10][CH:9]=2)[CH2:3]1.[CH3:26][C:27]([S:30]([NH2:32])=[O:31])([CH3:29])[CH3:28].O>C(OCC)(=O)C.C(O[Ti](OCC)(OCC)OCC)C>[F:25][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11](=[CH:10][CH:9]=2)[CH2:12][C:13]2([CH2:18][CH2:19][CH:20]([O:23][CH3:24])[CH2:21][CH2:22]2)[C:14]3=[N:32][S:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])[CH2:3]1
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=NS(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
6′-((3,3-Difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 14, 1.85 g, 5.28 mmol) and 2-methylpropane-2-sulfinamide (1.15 g, 9.50 mmol) were dissolved in 2-Me THF (40 mL). Tetraethoxytitanium (2.21 mL, 10.6 mmol) was added and the resulting mixture was heated to 80° C. over a weekend. The reaction mixture was cooled to r.t., and diluted with ethyl acetate (85 mL). Water (3 mL) was added under vigorous stirring and then the mixture was allowed to stand for 1 h. The mixture was filtered, the solvent was evaporated and the residue was purified by column chromatography on silica using a gradient of 0-70% ethyl acetate in heptanes. The product was recrystallized twice from EtOH. to give 0.750 g of the title compound (31% yield). MS (ES+) m/z 454 [M+H]+.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([CH2:28][CH2:29][O:30]C)[N:25]=[C:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.B(Br)(Br)Br.O.Cl[CH2:43]Cl>>[C:32]([C:24]1[N:23]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][C:6](=[O:5])[CH3:43])[CH2:9][CH2:10]3)[CH2:17][CH2:18]2)[CH:27]=[C:26]([CH2:28][CH2:29][OH:30])[N:25]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)CC2)nc(C(C)(C)C)n1
Reactant: ClCCl
Agent: BrB(Br)Br
Solvent: O
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cc(CCO)nc(C(C)(C)C)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of trans-N-[4-(2-{4-[2-tert-butyl-6-(2-methoxy-ethyl)-pyrimidin-4-yl]-piperazin-1-yl}-ethyl)-cyclohexyl]-acetamide from example 1 were dissolved in 5 mL of dichloromethane. At −20° C., 1.122 mL of 1 M BBr3 in dichloromethane was added dropwise. The reaction mixture was allowed to warm to room temperature and to stir overnight. Water was added, the organic phase removed and the aqueous phase adjusted to pH 7 with 5% aqueous sodium bicarbonate solution. Ethyl acetate was added, the organic layer removed, and the aqueous phase extracted three times with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent removed to yield 0.035 mg of crude product which was further purified via silica gel chromatography to yield 0.017 mg of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.[NH2:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:47]=[CH:48][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71])=[O:57])=[O:53])=[CH:59][CH:60]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
TBTU (0.021 g, 0.067 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.030 g, 0.056 mmol) and N-methyl morpholine (0.017 g, 0.166 mmol) in CH2Cl2 (5 ml) at 30° C. After 1.5 h, D-tert-leucine (0.011 g, 0.083 mmol) was added. Full conversion to the corresponding amide was obtained after 30 minutes. The reaction was quenched by the addition of water (1 ml). After 10 minutes, MeOH (3 ml) and NaBH (0.042 g, 1.11 mmol) were added. After 5 minutes, the reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). The reaction mixture was concentrated and purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M N4OAc buffer. The title compound (0.025 g, 69%) was obtained as a colourless solid. M/z: 654.0 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 0.86 (s, 9H), 2.82-2.98 (m, 2H), 3.76-3.81 (m, 2H), 3.92-3.96 (m, 1H), 4.26-4.33 (m, 1H), 4.52 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.97-7.37 (m, 12H), 7.58-7.63 (m, 1H), 8.29-8.34 (m, 1H).
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][C:9]([C:11]1[C:12](=[O:26])[C:13]([CH3:25])([CH3:24])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][C:17]([Cl:22])=[C:16]([Cl:23])[CH:15]=2)=[O:10]>C(O)(=O)C.O.O>[Cl:23][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[Cl:22])[C:20]([OH:21])=[C:11]([C:9](=[O:10])[CH2:8][CH2:7][CH:2]=[O:1])[C:12](=[O:26])[C:13]2([CH3:25])[CH3:24]
Reactant: CC1(C)C(=O)C(C(=O)CCC2OCCCO2)=C(O)c2cc(Cl)c(Cl)cc21
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)C(C(=O)CCC=O)=C(O)c2cc(Cl)c(Cl)cc21
Temperature: 95 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 3-(3-(1,3-dioxan-2-yl)propanoyl)-6,7-dichloro-4-hydroxy-1,1-dimethylnaphthalen-2(1H)-one (0.26 g, 0.65 mmol) in 25 mL acetic acid/water (4:1) was warmed to 95° C. and stirred for 1 hour. The mixture was treated with 10 mL water and stirred at 95° C. for another 30 minutes. The reaction mixture was diluted with 20 mL water and cooled to room temperature. The resulting mixture was then diluted with 200 mL additional water. The precipitate that formed was filtered and washed with 20 mL H2O. The crude precipitate was dissolved in 100 mL DCM, washed with 20 mL saturated NH4Cl, dried over anhydrous Na2SO4, and concentrated to give 0.22 g of the product as a pale yellow solid. MS m/e: 341 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: C1CCNC1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N3CCCC3)cc2)cc1

Procedure:
10.0 g (0.043 mol) of 4-bromobiphenyl were suspended in 600 ml of toluene together with 3.7 g (0.052 mol) of pyrrolidine and 6.2 g (0.0642 mol) of sodium tertiary-butoxide and 900 mg of the catalyst dichlorobis(tritolylphosphine)palladium(II) were added. The mixture was heated to reflux for 8 h, cooled, treated with water/ethyl acetate, and the organic phase was washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in approximately 300 ml of tertiary-butyl methyl ether and the hydrochloride of the product was precipitated by addition of 50 ml of 1N ethereal HCl.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17](O)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21].C(Cl)(=O)C([Cl:25])=O.CN(C=O)C>ClCCl>[F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([Cl:25])=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21]
Reactant: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (17) (347 mg, 1.2 mmol) in dry dichloromethane (2 mL) was stirred under nitrogen. Oxalyl chloride (453 mg, 3.6 mmol, 300 μL) was added followed by a drop of DMF. The reaction mixture was stirred at RT under nitrogen for 2 h then evaporated in vacuo to give 371 mg (quantitative) of 9-(2-fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride as a gum which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 20.2, 21.7, 26.4, 43.3 (d, JCF=23 Hz), 54.9, 80.5, 83.1, 100.2, 102.2, 105.8, 116.7, 122.4, 135.5, 137.4, 153.5, and 176.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CCO.[Ni]>[C:1]([O:5][C:6](=[O:22])[C@@H:7]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(C)[C@H](NCc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of (2S)-3-methyl-2-(2-nitro-benzylamino)-butyric acid tert-butyl ester (1.753 g, 5.68 mmol) in EtOH (30 mL) was added Raney nickel (1.3 mL) and the reaction mixture was hydrogenated under ballon pressure for 2 hours. The catalyst was filtrated and the filtrate evaporated to give the sub-title compound as a yellow oil (1.573 g, 100%). 1H NMR (400 MHz CDCl3) δ 0.81-0.90 (6H, m), 1.55 (9H, s), 1.90 (1H, m), 2.89 (1H, d), 3.62 (1H, d), 3.86 (1H, d), 4.68 (2H, vbr s), 6.68 (2H, m), 7.02 (1H, d), 7.13 (1H, t).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[OH:19][CH2:20][CH2:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.ClC1N=CC(C#N)=CC=1.NC(O)C>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([O:19][CH2:20][CH2:21][NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: N#Cc1ccc(NCCO)nc1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Agent: CC(N)O
Agent: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCOc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
In analogy to the procedure described for Example 90, 35 mg (48% of theory) of the product are obtained starting from 50 mg (0.17 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo-[1,2-c]pyrimidine (Example 6A) by reaction with 38 mg (0.23 mmol) of 6-[(2-hydroxyethyl)amino]pyridine-3-carbonitrile, which can be prepared in analogy to the synthesis of Example 48A from 6-chloropyridine-3-carbonitrile and aminoethanol, after subsequent purification by preparative HPLC.