Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=3)[CH:7]=[C:6]2[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].CCO.O>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=3)[CH:7]=[C:6]2[C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(C3CCC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc2cc(-c3ccc(N)cc3)n(C3CCC3)c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of 1-cyclobutyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole (0.83 g, 2.60 mmol), iron powder (0.84 mg, 15.0 mmol), ammonium chloride (0.96 g, 18.0 mmol), and EtOH/water (25 mL/8 mL) was stirred at 80° C. for 1 h and concentrated. The residue was suspended in DMF (20 mL) and MeOH/CH2Cl2 (1:1, 20 mL). The mixture was passed through a Celite pad, washed with MeOH/CH2Cl2 (1:1), concentrated and water was added to afford a precipitate which was collected by filtration and washed with water. The solid was dissolved in CH2Cl2, dried over MgSO4, concentrated and purified on silica gel (EtOAc/hexane 20%) to provide 4-(1-cyclobutyl-6-methoxy-1H-indole-2-yl)-phenylamine (0.57 mg, 75%) as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromoanisole
Reaction SMILES: [N:1]1([C:6]2[CH:20]=[CH:19][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]([N:25]=[C:26]=[S:27])[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[CH2:21]([NH:25][C:26]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14]1)=[S:27])[CH2:22][CH2:23][CH3:24]
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Reactant: CCCCN=C=S
Solvent: ClCCl
Product: CCCCNC(=S)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-[4-(1H-Imidazol-1-yl)benzoyl]-4-piperidinamine (4.06 g, 15.0 mmol) and butyl isothiocyanate (1.81 mL, 1.73 g, 15.0 mmol) are combined in methylene chloride (75 mL) and stirred at room temperature. After 24 hr, an additional portion (0.90 mL, 0.86 g, 7.5 mmol) of butyl isothiocyanate is added, and the mixture is stirred for 48 hr. The mixture is washed twice with 1N aqueous sodium hydroxide, once with brine, dried over magnesium sulfate, and evaporated. Trituration of the residue with ether and recrystallization from ethanol-ether affords the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Br)=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].BrCCBr.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.Cl>C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[B:21]([OH:26])[OH:22])=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)n1nnnc1-c1ccccc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)n1nnnc1-c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
To dry Mg turnings (76 mg, 3.13 mmol) in THF (1 mL) was added a solution of 1-tert-butyl-5-(2-bromophenyl)-1H-tetrazol (733 mg, 2.61 mmol) in THF (1.5 mL). 1,2-Dibromoethane (20 μL) was added and the mixture was warmed slightly with a heat gun. After 5 min, triisopropyl borate (564 mg, 3.00 mmol) was added and the mixture was stirred at room temperature for 23 h. Ice and and 0.5N HCl (7 mL) were added and the mixture was stirred at for 5 min. The mixture was extracted with ether, and the combined extracts were extracted with 1N KOH (10 mL). The aqueous extracts were filtered and acidified to pH 3 with 2N HCl. The precipitate was collected by filtration to give 306 mg (48%) of product as an off-white solid, mp 112°-115° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>O1CCOCC1>[Br:23][C:20]1[CH:19]=[C:15]2[C:14](=[CH:22][CH:21]=1)[N:13]=[C:2]([OH:4])[N:18]=[C:16]2[OH:17]
Reactant: NC(=O)c1cc(Br)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Oc1nc(O)c2cc(Br)ccc2n1
Temperature: 100 °C
Yield: 164.5 %

Procedure:
Triphosgene (173 g, 0.58 mmol) was added to a solution of 2-Amino-5-bromobenzamide (250 mg, 1.162 mmol) in 1,4-dioxane (12 mL). The reaction was heated at 100° C. for 1.5 hours, cooled to room temperature and quenched with water (1 ml). The solid was filtered and washed with EtOAc twice to provide crude product (230 mg), which was used without further purification.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.[OH-].[K+].[Br-].[CH3:15][O:16][CH:17]([O:25][CH3:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][O:25][CH:17]([O:16][CH3:15])[C:18]1[CH:19]=[CH:20][C:21]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:22][CH:23]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc(-c2cccnc2)cc1
Yield: 73 %

Procedure:
The starting aldehyde was obtained as follows: Diethyl 3-pyridylborane (1.51 g), powdered potassium hydroxide (1.71 g) and teteramethylammonium bromide (330 mg) were added to a solution of tetrakistriphenylphosphine palladium [0] (528 mg) and 4-bromobenzaldehyde dimethyl acetal (3.55 g) in anhydrous tetrahydrofuran (60 ml). The mixture was heated at reflux for 2 hours, the THF evaporated and the residue dissolved in ether (200 ml). The ether solution was washed with saturated brine (2×100 ml), dried (Na2SO4) and evaporated to an oil. The oil was purified by column chromatography on alumina, eluting with 10% ethyl acetate in hexane to give 4-(3-pyridyl)benzaldehyde dimethyl acetal (1.72 g). NMR(CDCl3): 3.37(6H,s), 5.45(1H,s), 7.45(1H,m), 7.58(4H,m), 7.89(1H,m), 8.59(1H,dd) and 8.85(1H,d). This diacetal (5.0 g) was stirred in 1M aqueous hydrochloric acid (30 ml) for 45 minutes and the mixture neutralised with 1M aqueous sodium hydroxide solution (30 ml) and extracted with ether (3×60 ml). The ether extracts were combined, washed with saturated brine, dried (Na2SO4) and evaporated to give 4-(3-pyridyl)benzaldehyde (3.41 g) as an oil which gave a solid on standing, m.p 48°-51° C.; NMR(CDCl3): 7.43(1H,q), 7.76(2H,m), 7.92(1H,m), 8.01(2H,m), 8.65(1H,dd), 8.90(1H,d) and 10.09(1H,s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH2:30]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:30][CH3:29])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3 carboxylate (Preparation 27) (4.70 g, 11.9 mmol) In ethanol (80 ml) was treated with methylamine (33% w/v in ethanol, 12.0 ml, 96.0 mmol) and the solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (9:1) gradually changing to dichloromethane:ethyl acetate (8:2) to afford the title compound as a pale yellow oil which crystallised on standing (4.23 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: O=C1C=CCC1
Product: O=C1CC[C@@H](c2ccc(OCc3ccccc3)c(F)c2)C1
Yield: 68.6 %

Procedure:
[4-(Benzyloxy)-3-fluorophenyl]boronic acid (5.00 g, 20 mmol) and cyclopentenone (0.85 mL, 10 mmol) were used and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (1.95 g, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Reaction time: 8 h

Procedure:
3-Nitrobenzaldehyde (2.04 g, 13.5 mmol) was dissolved in 50 ml 1,2-dichloroethane. 1-Acetylpiperazine 1.90 g, 14.9 mmol) and sodium triacetoxyborohydride (3.15 g, 14.9 mmol) were added followed by the addition of 0.100 ml of acetic acid. The reaction was allowed to proceed overnight (18 hours) and was then quenched with half-saturated NaHCO3 (aq). The mixture was extracted 3× with DCM and the organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluting with 95:5 DCM/MeOH) to afford 1-acetyl-4-(3-nitrobenzyl)piperazine (5-2). 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 8.13 (dd, J=1.2, 8.3 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 3.63 (t, J=5.2 Hz, 2H), 3.61 (s, 2H), 3.48 (t, J=4.8 Hz, 2H), 2.44 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.C(N(CC)CC)C.Cl[SiH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1>[CH3:23][C:22]([CH3:24])=[CH:21][SiH2:20][O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: CC(C)=C[SiH2]Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)=C[SiH2]OC1C2CC3CC(C2)CC1C3

Procedure:
2-Tricyclo[3.3.1.13,7]decanol (25 g), triethylamine (28 g) and toluene (250 g) were charged in a four-necked 500 ml flask, and then chlorodimethylvinylsilane (30 g) was dropwise added to the mixture at 40° C. over one hour while well stirring. The mixture was stirred at 40° C. for 7 hours with monitoring the progress of the reaction by gas chromatography. After the completion of the reaction, a 4% hydrochloric acid (300 ml) was added to the reaction mixture, and then the mixture was separated. The organic layer was washed with water and concentrated by evaporating off toluene contained in the organic layer, and the residue was distilled under reduced pressure to obtain 2-dimethylvinylsiloxy-tricyclo[3.3.1.13,7]decane having the following structure (40 g):
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:20][CH:21]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a mixture of glycine t-butyl ester hydrochloride (0.84 g, 5 mmol), and 4-benzyloxy-benzaldehyde (0.53 g, 2.5 mmol) in CH2Cl2 (25 mL) at 0° C. was added sodium triacetoxyborohydride (0.81 g, 3.8 mmol). The mixture was allowed to warm to room temperature and stirred overnight. Aqueous NaHCO3 was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted 3 times with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography (ethyl acetate) gave 0.38 g (59%) of the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:2].[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
55 mg (0.11 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl]-[1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 27.3 mg (0.14 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile hydrochloride (Example 2A) and 0.12 ml (0.69 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 28 mg (43% of theory) of the product as a solid.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][N:15]([CH2:17][CH2:18][C@@H:19]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:20][N:21]([CH3:35])[C:22](=[O:34])[C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Br:33])[CH:24]=4)[CH2:14]3)[CH2:9][CH2:8]2)=[O:6])CCC1.N1CC(N2CCC(C(N)=O)CC2)C1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Br:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=1)[C:22]([N:21]([CH3:35])[CH2:20][C@H:19]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:18][CH2:17][N:15]1[CH2:14][CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([NH2:1])=[O:6])[CH2:8][CH2:9]2)[CH2:16]1)=[O:34]
Reactant: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: NC(=O)C1CCN(C2CNC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCC(C(N)=O)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.5 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 1.00 g, 2.24 mmol) and 1-azetidin-3-ylpiperidine-4-carboxamide (see method 4; 0.49 g, 2.69 mmol) and triethylamine (1.24 mL, 9.0 mmol) were dissolved in methylene chloride (30 mL) together with methanol (5 mL). To the resultant solution was added sodium cyanoborohydride (0.21 g, 3.36 mmol) and the mixture was stirred at RT for 20 min. The solvent was removed by evaporation and the residue was partitioned between methylene chloride and saturated aqueous NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (ammonia saturated methanol/methylene chloride, 1-20% methanol). There was obtained 0.24 g (17%) of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.4-3.8 (cm, 23H), 5.7 (b, 1H), 5.8 (b, 1H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 614 (M+1)+.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)=[O:18])[CH2:12]1
Reactant: CN(CCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)morpholine-4-carboxylate (step 1) (0.9984 g, 2.232 mmol) and triflouroacetic acid (6.88 ml, 89 mmol) in DCM (7.44 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (7.44 ml) and washed with water followed by sat NaHCO3. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>O>[CH2:36]([N:33]([CH2:34][CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH2:38][CH3:39])[CH2:24][CH3:25])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:37]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(C)c1
Temperature: 40 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)benzoic acid (12.48 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (10.56 g.) and acetic anhydride (12 ml.) was warmed (at 40±8° C.) during one hour, diluted with water (50 ml., then 100 ml.), adjusted to pH 4.6 and filtered. The filtrate was clarified with water and adjusted to pH 5.5. Recrystallization of the resulting product (m.p. 134°-140° C.) from methanol afforded 3-(2,4-bis(diethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X = Y4 = (CH3CH2)2N, Y2 = CH3, Z4 = Z5 = Z6 = Z7 = H) (m.p. 149°-151° C.).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[C:23](O)=[O:24])=[CH:7][CH:6]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH3:48][O:49][C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[NH2:52].Cl>O.CN(C=O)C>[CH3:48][O:49][C:50](=[O:55])[C:51]([CH3:54])([NH:52][C:23]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[O:12][CH2:11][C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:27])([F:26])[F:1])=[CH:6][CH:7]=1)=[O:24])[CH3:53]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to 115 mg 1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carboxylic acid in 2 mL of abs. DMF 82 mg EDC, 45 mg 1-hydroxybenzotriazole and 49 mg N,N-diisopropylethylamine were added. After 30 min at 0° C. 56 mg of 2,2-dimethylglycine methyl ester hydrochloride and 49 mg N,N-diisopropylethylamine were added. The mixture was stirred for 16 h at room temperature. The mixture was poured into cold water, acidified to pH 3 with 2M HCl, extracted with ethyl acetate, washed with sat. sodium hydrogen carbonate solution and brine, dried over magnesium sulphate, filtrated and concentrated in vacuo to provide 124 mg of 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-propionic acid methyl ester.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1>C(O)C>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCO
Product: O=C(O)Cc1ccc(NC(=O)c2ccccc2)cc1
Yield: 52 %

Procedure:
Prepared analogously to Example 4a) from benzoylchloride and 4-aminobenzene acetic acid in a yield of 52% of theory. Colourless crystals, Mp. 207-208° C. (ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:23])[C:21]4[CH:25]=[C:26]([O:29][C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:28][C:20]=4[F:19])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cc(OC(F)(F)F)ccc1F
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(OC(F)(F)F)ccc1F
Yield: 11.7 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-fluoro-5-trifluoromethoxy-benzoyl chloride to afford the title compound (11 mg, 11.7%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=5.9 Hz), 6.91-6.94 (m, 1H, Harom), 7.41-7.44 (m, 2H, Harom), 7.50-7.53 (m, 2H, Harom), 7.67-7.69 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 10.65 (s, 1H, NHamide), 11.18 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=4.65 minutes, m/z: 449.08 (M+H)+, calculated for C20H13N4O4F4. HRMS (EI): m/z [M+H] calculated for C20H13N4O4F4: 449.0873; found: 449.0873.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14]>C(O)C>[C:2]([N:6]1[C:13]([OH:14])=[CH:12][C:11]([C:10]([F:20])([F:19])[F:9])=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CC(C)(C)n1nc(C(F)(F)F)cc1O
Yield: 59.1 %

Procedure:
373.8 g (3.0 moles) of tert-butylhydrazine hydrochloride and 50 ml of concentrated hydrochloric acid were added to a solution of 552.3 g (3.0 moles) of ethyl trifluoroacetoacetate dissolved in 1,500 ml of ethanol. The mixture was refluxed for 2 days with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 369.0 g (yield: 59.1%) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol as a white powder.