Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:20]([CH3:22])[CH3:21])[C:10]([C@H:12]1[C@H:16]([CH3:17])[C:15](=[O:18])[NH:14][C:13]1=[O:19])=[O:11])=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[NH2:8][C@@H:9]([CH:20]([CH3:22])[CH3:21])[C:10]([C@H:12]1[C@H:16]([CH3:17])[C:15](=[O:18])[NH:14][C:13]1=[O:19])=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)[C@@H]1C(=O)NC(=O)[C@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)[C@@H]1C(=O)NC(=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution, cooled at 0° C., of 4.40 g (14.09 mmol) of (3R,4S)-3-[(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedione (preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643) in dioxane is admixed dropwise with 35 ml of 4N hydrochloric acid solution in 1,4-dioxane. When the addition is at an end the mixture is warmed to room temperature and stirred for 2 h, after which the mixture is concentrated under reduced pressure. The crude product can be used directly in the next stage. If desired the residue is treated with diethyl ether and the crystals precipitated are filtered off and dried under a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: C[C@H](CCCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Product: C[C@H](CCCN1CCOCC1)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 87 %

Procedure:
4-chloro-N-(5-chloro-2-fluorophenyl)-N-[4-(morpholinyl)-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[4-(methylsulfonyl)methyl]-1-piperidinyl]-1(R)-methylbutyl]benzenesulfonamide by reacting 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[4-bromo-1(R)-methylbutyl]benzenesulfonamide with morpholine. Yield=87%; MS (ESI+), 475 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]2[C:37]2([OH:40])[CH2:38][CH2:39][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:35][CH2:36]2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C2(O)CCN(Cc3ccccc3)CC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
A solution of lithium diisopropylamide (15.5 mMol in tetrahydrofuran) was added via cannula to a solution of 4.0 gm (15.5 mMol) 1-phenylsulfonyl-1H-indole in 100 mL tetrahydrofuran at -78° C. The reaction mixture was stirred at this temperature for 1.5 hours, warmed to room temperature for 1 hour and then cooled again to -78° C. To this solution was then added a solution of 2.94 mL (15.9 mMol) 1-benzyl-4-piperidinone in tetrahydrofuran and the resulting mixture was allowed to warm to room temperature over 18 hours. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The phases were separated and the organic phase washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a dichloromethane gradient containing 0-2% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 3.23 gm (47%) of the desired compound as an off-white solid.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)[C:7](=[O:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1CCCCC1>[CH3:15][CH:5]1[C:4]2([C:1]([CH3:3])=[CH2:2])[CH2:13][CH:8]([CH:9]([CH3:12])[CH2:10][CH2:11]2)[C:7]2([O:18][CH2:17][CH2:16][O:14]2)[CH2:6]1
Reactant: OCCO
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: C=C(C)C12CCC(C)C(C1)C1(CC2C)OCCO1
Yield: 104.7 %

Procedure:
A soln. of 2.0 g of 5-isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (9.8 mmol) in 100 ml cyclohexane was treated with 1.8 g ethyleneglycol (2.9 mmol, 3.0 eq.) and 0.2 g para-toluenesulfonic acid mono hydrate (1.0 mmol 0.1 eq.). The soln. obtained was heated at reflux for 3 h (Dean-Stark apparatus), cooled and poured into aq. sat. NaHCO3 soln. (100 ml). Extraction with MTBE (2×80 ml) followed by washing of the aq. phases with H2O (100 ml) and aq. sat. NaCl soln. (150 ml), drying of org. phases over MgSO4 led to 2.6 g of crude product. FC (SiO2, hexane/MTBE 19:1) gave 0.76 g (31%) of compound 6 as colorless liquid. The boiling point of the end product is 130° C. at 0.09 mbar. Rf (hexane/MTBE 19:1) 0.47.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:5]([CH2:15][CH2:16][C:17]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(O)=O.[Na+].CCOC(C)=O.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:15][CH2:16][C:17](=[O:18])[N:19]2[C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1
Reactant: O=C(CCc1ccc(Br)nc1-c1ccccc1Cl)Nc1c(Cl)cccc1Cl
Agent: [Cu]I
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2c(cc(Br)nc2-c2ccccc2Cl)N1c1c(Cl)cccc1Cl
Temperature: 155 °C

Procedure:
To a suspension of 7.54 g of 3-[6-bromo-2-(2-chlorophenyl)pyridin-3-yl]-N-(2,6-dichlorophenyl)propanamide in 100 mL of DMF was added CuI (3.82 g) and powdered, dried K2CO3 (3.70 g). The mixture was heated to 155° C. for 30 min, then cooled and diluted with 250 mL of half-saturated NaHCO3 and 100 mL of EtOAc. The phases were separated and the aqueous phase was extracted 2×50 mL of EtOAc. The combined organics were washed with brine, dried (Na2SO4), and concentrated. The reside was purified by flash chromatography on a Biotage 65M column, eluting with a gradient system of 99:1 CH2Cl2-acetone to 97:3 CH2Cl2-acetone to yield the title compound as an off-white solid. Mass spectrum (ESI) 483 (M+1). 1H NMR (500 MHz, CDCl3): δ 2.72-2.92 (m, 3H); 2.96-3.06 (m, 1H); 6.37 (s, 1H); 7.39-7.54 (m. 2H); 7.56-7.60 (m, 2H).
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O)([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:6][CH3:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1C(C)(C)C
Reaction time: 16 h

Procedure:
Dimethylsulfate (56.7 g, 0.45 mol) was added at room temperature to a well-stirred mixture of 2-tert-butylphenol (45 g, 0.3 mol), CH2Cl2 (200 ml), 40% aq. NaOH (200 ml) and tetrabutylammonium bromide (1 g). After 16 h of stirring, the organic phase was separated, washed with H2O, dried over MgSO4, evaporated and distilled at 110-112° C./10 Torr. Yield 35 g (71%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(4-hydroxyphenyl)propanoate (275 mg, 1.42 mmol) in acetic acid (2 mL) was added nitric acid (60-62%, 300 mg, 2.86 mmol) at room temperature. The mixture was stirred for 1 hour at 50° C. and cooled to room temperature. The reaction mixture was poured into ice water (20 mL) and extracted with EtOAc. The organic layer was dried with MgSO4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=6/1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH2:16][C@H:15]2[C@H:11]([CH2:12][C@@H:13]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C@H:14]2/[CH:17]=[CH:18]/[CH:19]([OH:27])[C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:10]=1)=[O:4]>CC(C)=O>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@H:14](/[CH:17]=[CH:18]/[CH:19]([OH:27])[C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:12]2)=[O:4]
Reactant: CCCCC(F)(F)C(O)/C=C/[C@H]1[C@H]2CC(C=CCCC(=O)OC)=C[C@H]2C[C@H]1OC1CCCCO1
Solvent: CC(C)=O
Product: CCCCC(F)(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
(1S,5S,6S,7R)-3-[4-Methoxycarbonyl-1(EZ)-butenyl]-6-[4,4-difluoro-3(RS) hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxybicyclo[3.3.0]oct-2ene (17) (0.184 g) was dissolved in acetone and the solution was placed in an autoclave, into which tricarbonyl chromium/methyl benzoate complex (0.021 g) was added, and then the autoclave was degassed. The mixture in the autoclave was stirred under hydrogen pressure (70 kg/cm2) at 120° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified on column chromatography (hexane/ethyl acetate=7/2-3/1) to give (1S,2S,3R,5S)-(E)-7-(4-methoxycarbonylbutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E) -1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (18) as a colorless oily product. Yield: 0.175 g (95%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:14]([CH3:15])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN(c1ccccc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccccc1Br)C1CCNCC1
Yield: 109 %

Procedure:
To a solution of 4-(2-bromophenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 0.00562 mole), in DMF (10 mL) was added NaH (60% w/w dispersion in oil) (0.9 g, 0.02251 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (3.19 g, 0.0225 mole) was then added and stirring was continued for 30 minutes at ambient temperature. The reaction mixture was quenched with aqueous NH4Cl solution and the product was extracted with ether. The ether layer with washed with aqueous NaHCO3 solution followed by brine solution. The ether layer collected was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with ether and dried to afford 0.893 g (45%) of 4-[(2-bromo-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.6-7.54 (m, 1H), 7.28-7.2 (m, 1H), 7.14-7.08 (m, 1H), 6.96-6.88 (m, 1H), 4.2-4.0 (m, 2H), 3.3-3.2 (m, 1H), 2.8-2.7 (m, 2H), 2.7 (s, 3H), 1.7-1.6 (m, 2H), 1.6 (m, 1H), 1.45 (s, 9H). A solution of 4-[(2-bromo-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 0.0024 mole) in dioxane.HCl was stirred for 30 minutes. The reaction was concentrated under reduced pressure to afford 0.704 g (95%) of (2-bromo-phenyl)-methyl-piperidin-4-yl-amine. 1H NMR (DMSO-d6): δ 9.0 (bd, 3H), 7.6 (m, 1H), 7.4 (m, 2H), 7.0 (m, 1H), 3.2 (m, 3H), 2.9 (m, 2H), 2.6 (s, 3H), 1.9 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=3)=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Br)c2)c(Cl)c1CC
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)c3ccc(F)cc3)c(Br)c2)c(Cl)c1CC
Yield: 89.2 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) propionate (70 mg) was coupled with p-fluorobenzoyl chloride (35 mg), using the method described in Example 1(h). After recrystallization (ethyl acetate/petrolium ether), 80 mg of ethyl(3,5-dichloro-4-[3-bromo-4-p-fluorobenzamidophenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 60 mg of 3,5-dichloro-4-(3-bromo-4-p-fluorobenzamidophenoxy)phenylpropionic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:39]([CH:35]3[CH2:38][CH2:37][CH2:36]3)=[O:40])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)C1CCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)C1CCC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with cyclobutanecarbonyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H39N2O2Cl2 [(M+H)+] 577.2383, observed 577.2382.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:12]([CH3:22])[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:23]([NH:27][CH3:28])[CH2:24][CH2:25][CH3:26].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:23]([N:27]([CH3:28])[C:13]([N:12]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:22])=[N:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNC
Reactant: CN(C(=O)NC1CCCCC1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(C)C(=NC1CCCCC1)N(C)C1CCCCC1
Reaction time: 2 h
Yield: 38821.3 %

Procedure:
18.38 g of cyclohexyl isocyanate (0.147 mol) are added dropwise to a solution of 19.12 g of N-methyl-N-cyclo-hexylamine (0.169 mol) in 160 ml of hexane and then the cloudy mixture is refluxed for 2 h and then evaporated to dryness, to give 35 g of crude N,N′-dicyclohexyl-N-methylurea. 12 g of POCl3 (78 mmol) is added, over 1 h, to a suspension of 17 g of said N,N′-dicyclohexyl-N-methylurea (71.33 mmol) in 65 ml of toluene, and then, after a few hours at 20° C., 15.5 g of N-butyl-N-methyl-amine (0.178 mmol) are added over 2 h, and then, after a further 2 h at 20° C., 50 ml of water are added. 49 g of 35% sodium hydroxide are then added while cooling, and the two-phase medium is then extracted with diisopropyl ether. After drying and evaporation to dryness, the oil obtained, 26.5 g, is distilled at 180° C. under 1 mbar, to give 21.25 g of the expected guanidine (yield 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:47][CH2:48][C:49]([NH:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:50])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(N)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Nc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 100.2 %

Procedure:
tert-butyl 4-(4-(4-aminobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (100 mg, 0.204 mmol), 2-(2-(tert-butoxycarbonylamino)acetamido)acetic acid (56.8 mg, 0.245 mmol), HATU (116 mg, 0.306 mmol), and Hunig's Base (0.178 mL, 1.019 mmol) were stirred in DCM (3 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give tert-butyl 4-(4-(4-(2-(2-(tert-butoxycarbonylamino)acetamido)acetamido)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (144 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1C=CC=CC=1>[CH2:23]([O:22][C:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])[CH3:24]
Reactant: CN1Cc2c(N)cccc2C(c2ccccc2)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cccc2c1CN(C)CC2c1ccccc1
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of 5.5 g 0.023 mole of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline and 50 ml of anhydrous benzene a solution of 3.4 g (0.031 mole) of ethyl chloroformate and 30 ml of anhydrous benzene is added. The reaction mixture is heated to boiling for 3 hours, the benzene is distilled off in vacuo. The residue is dissolved in 5 ml of water, made alkaline with a 30% aqueous sodium hydroxide solution and extracted three times with 50 ml of chloroform each. The chloroform extracts are united, dried over sodium sulfate and evaporated. The residue is washed with some cold ethanol and recrystallized from ethanol. Thus 3.0 g of the title compound are obtained in the form of white crystals. Yield 37.5%. Mp.: 178° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH2:32][CH2:33][OH:34])[C:21]5[N:26]=[CH:25][C:24]([C:27](OCC)=[O:28])=[CH:23][N:22]=5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CO.[NH2:43][OH:44]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH2:32][CH2:33][OH:34])[C:21]5[N:26]=[CH:25][C:24]([C:27]([NH:43][OH:44])=[O:28])=[CH:23][N:22]=5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NO
Reactant: CCOC(=O)c1cnc(N(CCO)Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)nc1
Solvent: CO
Product: O=C(NO)c1cnc(N(CCO)Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)nc1

Procedure:
The title compound 86 was prepared (42 mg, 36%) as an off-white solid from 0505-86 (120 mg, 0.21 mmol) and freshly prepared hydroxylamine methanol solution (8.0 mL) using a procedure similar to that described for compound 3 (Example 1): m.p. 190-194° C. LCMS: 548 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 3.64 (dd, J1=10.8 Hz, J2=5.6 Hz, 2H), 3.79 (dd, J1=8.4 Hz, J2=4.4 Hz, 6H), 3.95 (t, J=4.4 Hz, 4H), 4.85 (t, J=5.2 Hz, 1H), 5.25 (s, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 8.21 (d, J=6.8 Hz, 1H), 8.74 (s, 2H), 8.87 (s, 1H), 9.07 (s, 1H), 11.13 (s, 1H), 13.20 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[N+:12]([O-])=O>[Pd]>[NH2:12][C:4]1[CH:5]=[C:6]([C:9](=[O:11])[CH3:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1ccc(C(C)=O)cc1N
Yield: 80.5 %

Procedure:
1-(3-Amino-4-methylamino-phenyl)-ethanone (66 mg) was prepared by following General Procedure B starting from 1-(4-methylamino-3-nitro-phenyl)-ethanone (97 mg) and Pd/C (10% by weight, 10 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:28][CH:27]6[O:29][CH:24]([CH2:25][CH2:26]6)[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl.CO>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([N:22]6[CH2:23][CH:24]7[O:29][CH:27]([CH2:26][CH2:25]7)[CH2:28]6)[CH:17]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CC7CCC(C6)O7)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CC5CCC(C4)O5)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 87 %

Procedure:
tert-Butyl [1-(4-{2-(2-aminopyridin-3-yl)-5-[3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)cyclobutyl]carbamate (62.1 mg, 0.0965 mmol) was dissolved in DCM (1 mL)-MeOH (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 1.25 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (54.8 mg, 87.0%) as yellow solid.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=2)[N:39]=[C:38]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[C:37]=1[CH3:53].[NH2:54][C:55]1[CH:56]=[C:57]([NH:67][C:68](=[O:70])[CH3:69])[CH:58]=[C:59]([N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45]([C:36]([NH:54][C:55]3[CH:56]=[C:57]([NH:67][C:68](=[O:70])[CH3:69])[CH:58]=[C:59]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)[CH:60]=3)=[C:37]([CH3:53])[C:38]([N:47]3[CH2:51][CH2:50][CH2:49][C:48]3=[O:52])=[N:39]2)=[CH:44][CH:43]=1
Reactant: CC(=O)Nc1cc(N)cc(N2CCOCC2)c1
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)ccc2c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(Nc2c(C)c(N3CCCC3=O)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X by stirring palladium (II) acetate (0.3 mg, 1.417 μmol), XPhos (2.0 mg, 4.25 μmol), 1-(4-chloro-7-fluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (0.020 g, 0.071 mmol), N-(3-amino-5-morpholinophenyl)-acetamide (0.020 g, 0.085 mmol), potassium carbonate (0.024 g, 0.177 mmol), and tert-butanol (0.5 mL) at 110° C. for 30 minutes. Purification by reverse-phase HPLC (0-70% acetonitrile in water) afforded N-(3-((7-fluoro-3-methyl-2-(2-oxo-1-pyrrolidinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)phenyl)acetamide as a yellow amorphous solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.80 (1H, dd, J=8.8, 7.3 Hz), 7.51-7.61 (1H, m), 7.45 (1H, br. s.), 7.08-7.19 (1H, m), 6.79-6.99 (1H, m), 6.37 (1H, br. s.), 6.25 (1H, br. s.), 6.05 (1H, br. s.), 4.13 (2H, d, J=7.1 Hz), 3.77 (4H, t, J=4.9 Hz), 3.08 (4H, t, J=4.9 Hz), 2.63 (2H, t, J=8.1 Hz), 2.23-2.36 (2H, m), 2.13 (3H, s), 2.06-2.10 (3H, m). Mass Spectrum (ESI) m/e=478.2 (M+1).