Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].C1COCC1.[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)[CH3:24]>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])=[O:14])[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.5 %

Procedure:
To a 50 mL volume two-necked flask, 3.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 20 ml of THF (anhydrous), 1.73 g of acetophenone and 780 mg of acetic acid were added under a nitrogen atmosphere, and the mixture was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure and hexane was added thereto. The precipitated crystals were collected by filtration and dried to give 3.77 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1-phenyl-1-ethylidene)hydrazine ((40-a)-(14)-7).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[CH2:28]/[CH:29]=[CH:30]\[CH2:31]Cl>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:17]([O:19][CH3:20])=[O:18])[CH2:31][CH:30]2[CH:29]=[CH2:28])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: ClC/C=C\CCl
Reactant: COC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CC1(C(=O)OC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step 1, above, (1.0 g, 3.4 mmol) in 10 ml THF at -20° C. was added a 1M solution of potassium t-butoxide in THF (3.73 ml, 3.73 mmol) over 15 minutes. After 30 minutes at -20° C., cis-1,4-dichlorobut-2-ene (0.393 ml, 3.73 mmol) was added dropwise and the reaction was warmed to room temperature. After 20 minutes the reaction was cooled to -20° C. and treated with potassium t-butoxide in THF (3.73 ml, 3.73 mmol). The reaction was allowed to warm to room temperature, then was heated at 50° C. for 30 minutes and quenched with saturated ammonium chloride solution. The solvents were removed in vacuo and the residue was taken up in ethyl acetate and washed with water. The organic layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, evaporation and gravity silica gel chromatography (SGC) with 2% ethyl acetate in petroleum ether as eluant, a mixture of the title compound and methyl 1-(4'-t-butyldimethylsilyloxymethylphenyl)-2-vinylcyclopropane-1-carboxylate (7:1 ratio, total 708 mg) was obtained as an oil. Since the two compounds were inseparable, the mixture was taken on.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([N:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccnn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccnn1-c1ccccc1
Yield: 81 %

Procedure:
4.4 g of ethyl 1-phenylpyrazole-5-carboxylate from Example 1 were stirred for 6 hours at room temperature with 10 ml of 16.5% strength aqueous NaOH and 10 ml of ethanol; the ethanol was removed by distillation, the aqueous phase was extracted twice with 10 ml of toluene, and the pH was adjusted to 3 using concentrated HCl. The precipitate was filtered off under suction, washed with a little water and dried: 3.1 g of product of boiling point 182°-183° C. were obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38](O)=[O:39])=[N:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:39])=[N:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)Cc1noc2ccccc12
Agent: Cl
Product: O=C(Cc1noc2ccccc12)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (114 mg, 93%), MS (ISP) m/z=490.4 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2-benzo[d]isoxazol-3-yl-acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[I:12]N1C(=O)CCC1=O>CC#N>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:12])[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1CCc2cc(O)ccc21
Solvent: CC#N
Product: O=C1CCc2cc(O)c(I)cc21

Procedure:
5-Hydroxy-1-indanone (1.48 g), N-iodosuccinimide (2.25 g) and CH3CN (20 ml) were stirred at room temperature overnight. The solution was evaporated to dryness, slurried with EtOAc, then filtered. The filtrate was evaporated to dryness and the solid recrystallized from CH3CN affording the desired compound (0.92 g), m.p. 114°-15° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH2:7]NC(C)(C)CO.ClN1C(=[O:29])CCC1=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH:7]=[O:29]
Reactant: CC(C)(CO)NCc1cc(Br)ccc1CCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=Cc1cc(Br)ccc1CCc1ccccc1
Reaction time: 4 h
Yield: 48.6 %

Procedure:
A mixture of 2-(N-(5-bromo-2-(phenethyl)benzyl)amino)-2-methylpropan-1-ol (9.13 g), N-chlorosuccinimide (3.38 g) and dichloromethane (50 ml) was stirred for 4 hours. Aluminia (10 g) was added and the mixture stirred for 6 days, filtered and the solvent evaporated. The residue was dissolved in dichloromethane (200 ml) and alumina (60 g) added in 6 portions over 8 hours. The mixture was filtered, the filtrate evaporated and the residue purified by MPLC eluting with dichloromethane/hexane (1:1) to give 5-bromo-2-(phenethyl)benzaldehyde (3.54 g).
Reaction SMILES: O=[C:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(NC(=O)O)C.[NH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C=CC(O)=CC=1)O.C1(C)C=CC=CC=1>[C:3]([C:2]([NH:18][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH2:11])(=[O:4])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: CCOC(N)=O
Agent: CCNC(=O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=C(NC(=O)OCC)C(=O)c1ccccc1
Reaction time: 2 h
Yield: 22.5 %

Procedure:
In a flame dried nitrogen purged 100 ml round bottom flask equipped with a magnetic stirring bar, Dean-Stark trap and a reflux condenser were added 3.0 g (20.3 mmol) α-keto-propiophenone, 3.6 g (40.5 mmol) urethane (ethyl carbamate),10 mg (0.1 mmol) hydroquinone, 60 mg (0.3 mmol) paratoluenesulfonic acid and 20 ml of toluene. The mixture was refluxed under nitrogen with vigorous stirring for 31/2 hours. The solvent was removed under reduced pressure and the residue distilled through a short path distillation column giving approximately 1 g of ethyl N-(1-benzoylvinyl)carbamate bp≃130°-135° C. (1mm).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].O.Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N2CCCc3ccc(C=O)nc32)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2, 150 mg, 0.424 mmol) in THF (3 ml) was treated with water (2.25 ml) and HCl conc. (0.75 ml). The reaction mixture was stirred for 15 min at room temperature. The reaction was quenched by addition of sat. aq. NaHCO3 (gas evolution) and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([CH:36]=[O:37])[CH:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.[Cl-].[NH4+]>[CH:22]1([O:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([CH:36]([OH:37])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:29]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1cnc(C=O)cc1OC1CCCC1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cnc(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
n-Butyllithium (3.21 mL of 2.5 M solution) is added to a solution of diisopropylamine (1.15 mL) in dry tetrahydrofuran (25 mL) with the temperature being maintained below −60° C. After 30 min a solution of 3,5-dichloro-4-methylpyridine (1.21 g) in tetrahydrofuran (7 mL) is added dropwise and the mixture stirred for a further 30 min. A solution of 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g) in tetrahydrofuran (7 mL) is added and the mixture stirred for 4 hours whilst being allowed to warm to room temperature. After a further 18 hours at room temperature the mixture is diluted with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate. The extracts are washed with water, dried (MgSO4) and evaporated to give a yellow oil. The oil is triturated with n-pentane to give (±)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanol (1.4 g) as an off-white solid, m.p.110-112° C. [1Hnmr in D6-DMSO shifts relative to Me4Si: 1.55-1.78, 6H, m; 1.95, 2H, m; 3.27, 2H, m; 3.79, 3H, s; 4.89, 2H, m; 5.64, 1H, d; 7.07, 1H, s; 7.98, 1H s; 8.54, 2H, s.].
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.O.NN>CO.[Ni]>[CH3:1][NH:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CNc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CNc1ccc2cccnc2c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a solution of N-methyl-8-nitroquinolin-7-amine (1.6 g, 7.9 mmol) in MeOH (25 mL) was added hydrazine hydrate (2.25 g, 455 mmol) and Raney Ni (8 drops). The mixture was stirred at room temperature for 20 minutes. The catalyst was removed by filtration and the filtrate was concentrated to give N7-methylquinoline-7,8-diamine as a yellow solid (1.2 g, yield 80%). ESI MS: m/z 174 [M+H]+.
Reaction SMILES: ClCCCC(C1C=CC2[N:11]([CH2:26][CH3:27])[C:12]3[C:17]([C:18]=2C=1)=CC(C(=O)CCCCl)=CC=3)=O.Cl[CH2:29][CH2:30][CH:31]([CH3:56])[C:32]([C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH2:54][CH3:55])[C:39]3[C:44]([C:45]=2[CH:46]=1)=[CH:43][C:42]([C:47](=[O:53])[CH:48]([CH3:52])[CH2:49][CH2:50]Cl)=[CH:41][CH:40]=3)=[O:33]>>[CH2:54]([N:38]1[C:37]2[CH:36]=[CH:35][C:34]([C:32](=[O:33])[CH:31]([CH3:56])[CH2:30][CH2:29][N:11]3[CH2:26][CH2:27][CH2:18][CH2:17][CH2:12]3)=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[C:42]([C:47](=[O:53])[CH:48]([CH3:52])[CH2:49][CH2:50][N:11]1[CH2:12][CH2:17][CH2:18][CH2:27][CH2:26]1)[CH:43]=2)[CH3:55]
Reactant: CCn1c2ccc(C(=O)C(C)CCCl)cc2c2cc(C(=O)C(C)CCCl)ccc21
Reactant: CCn1c2ccc(C(=O)CCCCl)cc2c2cc(C(=O)CCCCl)ccc21
Product: CCn1c2ccc(C(=O)C(C)CCN3CCCCC3)cc2c2cc(C(=O)C(C)CCN3CCCCC3)ccc21

Procedure:
Following the procedure of Example 6, only substituting for 3,6-bis(4-chlorobutyryl)-N-ethylcarbazole the appropriate molar equivalent amount of 3,6-bis(4-chloro-2-methylbutyryl)-N-ethylcarbazole, the desired product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@H:6]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].[Li+].[CH3:31][Si]([N-][Si](C)(C)C)(C)C.C1COCC1.CI.C(#N)C.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH3:31])[CH:6]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)[C@H](C)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (300 mg, 0.718 mmol) in THF (10 ml) at −78° C. is added LiHMDS/THF (1M) (1.579 ml, 1.579 mmol). The reaction mixture is stirred at −78° C. for 50 min and then to this mixture is added methyl iodine (0.054 ml, 0.861 mmol) and the reaction is slowly warmed up to room temperature and stirred over night. The reaction is quenched by sat. NH4Cl and is extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. Reverse phase HPLC [20 to 90% ACN—H2O (0.1% TFA) over 10 min by Sunfire C18] give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester. LCMS (condition B): 432 (M+1); retention time=1.55 min. To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester (240 mg, 0.556 mmol) in DCM (2 ml) at room temperature was added TFA (1.070 ml, 13.89 mmol) and the mixture is stirred at room temperature. 1 hr the reaction is done so the mixture is concentrated to give (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester trifluoroacetate. LCMS (condition B): 332 (M+1); retention time=1.00 min.
Reaction SMILES: [S:1]1[CH2:10][C:2]1([CH3:11])[CH:3]1[CH2:8][CH2:7][C:6]([CH3:9])=[CH:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[C:6]1([CH3:9])[CH2:7][CH2:8][CH:3]([C:2]([SH:1])([CH3:10])[CH3:11])[CH2:4][CH:5]=1
Reactant: CC1=CCC(C2(C)CS2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1=CCC(C(C)(C)S)CC1
Temperature: 0 °C
Yield: 69 %

Procedure:
0.637 g (3.8 mM) of the compound prepared according to letter (b) above in 12 ml of tetrahydrofuran (THF) were added under nitrogen atmosphere to a stirred boiling suspension of 72 mg (1.9 mM) of LiAlH4 in 3 ml of THF. The reaction mixture was refluxed for 1 further hour, then cooled at 0° C. and the excess of LiAlH4 decomposed by addition of water. The obtained mixture was then extracted with ether (3×) and the organic phase washed with water (3×), dried and evaporated. After fractional distillation of the crude residue, there were obtained 0.450 g (69% yield) of the desired 1-p-menthene-8-thiol, b.p. 40° C./0.133 Pa.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cccc(F)c1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Fluoro-2-nitrophenyl)-(3-fluorophenyl)amine (2.79 g, 11.16 mmol) was dissolved in EtOAc (110 mL) and the flask evacuated and flushed with nitrogen gas. 10% Pd/C (0.3 g) was added and the reaction mixture stirred under an atmosphere of hydrogen gas, at RT overnight. A further amount of 10% Pd/C (0.3 g) was added and the reaction mixture stirred under an atmosphere of hydrogen gas for an further 2 h. The resultant mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the title compound as a brown oil, which solidified on standing (2.57 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 7.17 (1H, td, J=8.16, 6.58 Hz), 6.94-6.87 (1H, m), 6.76-6.70 (2H, m), 6.62-6.47 (3H, m), 5.35 (1H, s), 3.54 (2H, s)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.CC#N>O>[C:28]([C@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([OH:30])=[O:29]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 17 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-tryptophan to provide the title compound in 17% yield as yellow needles (flash chromatography on SiO2, eluent MeCN, H2O, AcOH—20, 1, 0.3).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:33])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:11]3([CH2:23][N:24]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]4=[O:33])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:15][CH2:16]2)[CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Through a solution of 2-((1-Benzyl-4-(4-cyclopropylpiperazin-1-yl)-piperidin-4-yl)methyl)isoindolin-1-one (0.63 mmol) in ethanol (10 ml) was passed argon gas for 10 min. Then acetic acid (200 μl) and Pd(OH)2 (20% by weight) were added to the reaction mixture. The mixture was stirred at room temperature for 16 h under an atmosphere of H2 by using a hydrogen balloon. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness to give the desired product. Yield: 60%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:39]2[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A 50 mL, 2-neck round bottom flask was charged with tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (520 mg, 1.042 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (282 mg, 1.355 mmol), potassium carbonate (504 mg, 3.65 mmol), and DMA (3 mL). The reaction flask was degassed followed by addition of 1,1-bis(di-tert-butylphosphino)ferrocene palladium chloride (21 mg, 0.032 mmol). Under N2 atmosphere, the reaction mixture was heated in an oil bath at 80° C. for 2.5 h and then allowed to cool to RT. In a separate 50 mL recovery flask was added de-ionized H2O (12 mL) and the vessel was cooled in an ice/water bath. When the internal temperature of the water reached 2° C., the reaction mixture was transferred to the recovery flask at a rate which kept the internal temperature below 10° C. Following the addition, the reaction vessel was rinsed with DMA (1 mL). The rinse was added to the recovery flask and the resulting aqueous slurry was stirred in an ice bath for 10 min and was then allowed to warm to RT with stirring. When the internal temperature reached 22° C., the mixture was filtered. The filter cake was rinsed with de-ionized H2O (2×5 mL) and air-dried under suction. The solids were re-suspended in glacial acetic acid (3 mL) and stirred at RT for 1 h. Isopropanol (1 mL) was added and the mixture was stirred at RT. De-ionized water (3.4 mL) was added to induce crystallization. Precipitation occurred, but some solids were sticky, so the mixture was heated in a 40° C. oil bath, with stirring, for 20 min. The mixture was allowed to cool to RT with stirring and then filtered. The filter cake was rinsed with a 3:3:1 mixture of HOAc/H2O/IPA (2.1 mL), briefly air-dried under suction, and then dried in a vacuum oven at 60° C. to give the title compound as a tan solid (352 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9H), 1.53 (s, 9H), 1.65 (m, 3H), 1.76 (m, 3H), 3.94 (s, 3H), 4.03 (br s, 1H), 4.38 (br s, 1H), 4.67 (s, 2H), 5.12 (br s, 1H), 5.77 (br s, 1H), 8.25 (br s, 1H), 8.96 (br s, 1H). [M+H] calc'd for C27H37FN6O5, 545. found, 545.