Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(Oc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, phenol and DBU in THF. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([O:9][CH2:10][CH2:11][NH2:12])=[C:7]([CH:16]([CH3:18])[CH3:17])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:26][C:27]1[C:28]([CH3:39])=[C:29]([C:32]([O:37][CH3:38])=[C:33]([CH3:36])[C:34]=1[CH3:35])[CH2:30]Cl>CN(C)C=O>[OH:26][C:27]1[C:28]([CH3:39])=[C:29]([C:32]([O:37][CH3:38])=[C:33]([CH3:36])[C:34]=1[CH3:35])[CH2:30][NH:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[C:14]([CH3:15])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(=O)Nc1cc(C(C)C)c(OCCN)cc1C
Reactant: COc1c(C)c(C)c(O)c(C)c1CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(O)c(C)c1CNCCOc1cc(C)c(NC(C)=O)cc1C(C)C
Temperature: 25 °C
Yield: 5.8 %

Procedure:
2-(4-Acetylamino-2-isopropyl-5-methylphenoxy)ethylamine (1.0 g) and triethylamine (0.50 g) were dissolved in N,N-dimethylformamide (20 ml), and 3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl chloride (0.86 g) dissolved in N,N-dimethylformamide (10 ml) was added dropwise while stirring the mixture at room temperature. The mixture was stirred for 5 hours. After the completion of the reaction, the solvent was distilled off, and water and ethyl acetate were added. The mixture was stirred and an insoluble matter was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give 100 mg of the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:10]([NH:12][NH2:13])=[O:11]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:10]2[O:11][C:1](=[O:2])[NH:13][N:12]=2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc(-c2n[nH]c(=O)o2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 equivalents of a 20% phosgene solution in toluene were added dropwise to the solution of 850 mg of 3-methoxy-4-nitrobenzoic hydrazide (m.p.: 158.2° C., prepared from methyl 3-methoxy-4-nitrobenzoate and hydrazine hydrate in isopropanol at 80° C.) in 25 ml of dioxane and the mixture was stirred at room temperature for 1 hour. After concentrating, the residue was recrystallized from isopropanol, filtered off with suction and dried under reduced pressure.
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:11])C1C=CC=CC=1.C[OH:33]>[Pd]>[OH:18][C@H:17]1[C@H:16]([OH:19])[C@@H:15]([OH:20])[CH2:14][N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C@H:12]1[C:10]([OH:33])=[O:11]
Reactant: CO
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above compound (6) (88 mg) was dissolved in methanol (12 mL) and 10% Pd—C (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure, the resulting residue was freeze-dried to obtain the titled compound (60 mg) as a colorless amorphous.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4](=O)[O:3]1.S(O)(O)(=O)=O.[NH2:17][NH2:18]>O>[O:1]=[C:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4](=[O:3])[NH:18][NH:17]1
Reactant: NN
Reactant: O=C(O)CC1=CC(=O)OC1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc(=O)[nH][nH]c1=O
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of (2,5-dioxo-2,5-dihydro-3-furanyl)acetic acid (9 g) and hydrazine sulphate (7.2 g) in water was heated to reflux for 4 hours then allowed to cool to ambient temperature. The precipitate was filtered, washing with water then acetone. Drying in vacuo afforded a white solid (8.04 g, 82%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:5][CH:4]=1.C[C:27]1[C:37](C)=[CH:36][CH:35]=[CH:34][C:28]=1[CH2:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:19][C:18]1[C:23]([CH3:22])=[CH:24][CH:25]=[CH:10][C:11]=1[C:28]1([CH2:29][S:30]([N:2]([C:3]2[CH:4]=[CH:5][C:6]([N:9]3[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]4[C:18]5[C:23]([CH:24]=[CH:25][C:10]3=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:7][CH:8]=2)[CH3:1])(=[O:31])=[O:32])[CH:27]=[CH:37][CH:36]=[CH:35][CH2:34]1
Reactant: CNc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1cccc(CS(=O)(=O)Cl)c1C
Solvent: c1ccncc1
Product: Cc1cccc(C2(CS(=O)(=O)N(C)c3ccc(N4C(=O)CC(=O)Nc5c4ccc4ccccc54)cc3)C=CC=CC2)c1C
Yield: 55.9 %

Procedure:
5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40 mg, 0.121 mmol) obtained in Example 198, (1), and 2,3-dimethylbenzylsulfonyl chloride (132 mg, 0.605 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (20 mg, yield 32%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19](O)=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([N:32]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(N(CCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)CCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-3-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 91° to 93°).
Reaction SMILES: [CH2:1]([C:5]1[CH2:12][S:11][CH:10]2[N:7]([C:8](=[O:45])[CH:9]2[NH:13][C:14](=[O:44])[C:15](=[N:41][O:42][CH3:43])[C:16]2[N:17]=[C:18]([NH:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:19][CH:20]=2)[C:6]=1[C:46]([O:48]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:47])[C:2]([CH3:4])=[O:3].O>C(O)=O>[CH2:1]([C:5]1[CH2:12][S:11][CH:10]2[N:7]([C:8](=[O:45])[CH:9]2[NH:13][C:14](=[O:44])[C:15]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[N:41][O:42][CH3:43])[C:6]=1[C:46]([OH:48])=[O:47])[C:2]([CH3:4])=[O:3]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(C)=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CC(C)=O)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
A solution of the syn isomer of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g) in formic acid (42 cc) is heated to 50° C. Distilled water (15 cc) is added in the course of 15 minutes and the mixture is stirred for 15 minutes at 50° C. It is filtered and the filtrate is concentrated to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 20° C. The residue is taken up 3 times in succession with ethanol (50 cc), which is evaporated off to dryness each time under reduced pressure (1 mm Hg; 0.13 kPa) at 20° C. The solid residue is recrystallised from propan-2-ol (60 cc) and the crystals are filtered off, washed with diethyl ether (20 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 30° C. This yields the syn isomer of 3-acetonyl-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.2 g) in the form of beige crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=1
Reactant: Cc1ccc(Cl)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (6.2 g, 16.2 mmol) and DMAP (0.2 g, 1.62 mmol) in dry CH2Cl2 (70 mL), Et3N (8 g, 81 mmol) was added. The resulting mixture was cooled to 0-5° C. in ice-water bath, a solution of methyl chloroformate (3.1 g, 32.4 mmol) in dry CH2Cl2 (30 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. The reaction was quenched with water. The aqueous layer was extracted with CH2Cl2 (3×30 mL), the combined organic layers were washed with brine, then dried over Na2SO4, filtered and concentrated to give the crude product, which was firstly purified by column chromatography and then by preparative HPLC to give (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.5 g). 1H NMR (CD3OD, 400 MHz) δ 7.30 (s, 1H), 7.20-7.10 (d, 2H), 4.81 (s, 1H), 4.46-4.30 (d, 1H), 4.29-4.15 (d, 1H), 3.95-3.83 (d, 1H), 3.62 (s, 3H), 3.30 (s, 4H), 2.90-2.65 (dd, 2H), 2.30 (s, 3H), 1.70 (s, 1H), 1.59 (s, 1H), 1.41 (s, 9H), 1.35-1.20 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17](=O)[CH2:18][Cl:19])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>ClCCCl>[F:1][C:2]1[C:15]([N:16]=[C:17]([Cl:41])[CH2:18][Cl:19])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)CCl)cc21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: C#CCN1C(=O)COc2cc(F)c(N=C(Cl)CCl)cc21
Reaction time: 2 h

Procedure:
First, 1.00 g of N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-2-chloroacetamide, 2.25 g of triphenylphosphine polymer bound and 4 ml of carbon tetrachloride were dissolved in 35 ml of 1,2-dichloroethane, and then the reflux under heat was continued for 2 hr. After letting the solution stand to cool the same, the solid was filtered out, and then the solvent was distilled out under reduced pressure to quantitatively obtain N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-2-chloroacetimidoylchloride.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH2:27])=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH:27][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:16]1
Reactant: ClCCOc1cccc2ccccc12
Reactant: NCCCc1c[nH]c2ccccc12
Product: c1ccc2c(OCCNCCCc3c[nH]c4ccccc34)cccc2c1
Yield: 85 %

Procedure:
This compound was prepared in the manner described above for Example 13 by replacing 2-(indan-4-yloxy)-ethylchloride with 2-(napthalen-1-yloxy)-ethylchloride (0.6 g, 2.8 mmol), and 3-(5-fluoro-1H-indol-3-y-)-propylamine with 3-(1H-indol-3-yl)-propylamine (1.35 g, 7.2 mmol) in 85% yield (1.42 g) as a yellow solid: mp 119-120° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:18][CH3:24])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
A mixture containing 12.46 g of 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid and a catalytic amount of p-toluenesulfonic acid in 70 ml of methanol is boiled under reflux for 4 hours. After evaporating the solution to dryness, the residue is dissolved in ether and washed with sodium hydrogen carbonate solution. The ethereal layer is separated, dried over anhydrous magnesium sulfate and evaporated to dryness to give 11.5 g of product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>ClCCl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([CH2:8][Cl:14])=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cnc1Cl
Solvent: ClCCl
Product: COc1cc(CCl)cnc1Cl
Reaction time: 5 h

Procedure:
To a solution of (6-chloro-5-methoxypyridin-3-yl)methanol (0.50 g, 2.9 mmol) in dichloromethane (14 mL) at 25° C. was added thionyl chloride (230 μL, 3.2 mmol) dropwise. Let stir for 5 h, then the reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×). The combined organic layer were dried over MgSO4 and concentrated to furnish the product 2-chloro-5-chloromethyl-3-methoxypyridine that was 96% pure by GC-MS. The product was used immediately in the next step without further purification. GC-MS: Exact mass calcd for C7H7Cl2NO [M]+, 191. Found 191.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]([C:27]1[N:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:20]([C:27]1[N:32]=[CH:31][C:30]([CH2:33][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Oc5ccccc5)nc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-phenoxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-phenoxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:10][NH:11]C(=O)OCC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:11][CH2:10][C@@H:9]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CN(C)C(=O)C(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)[C@H](CN)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of benzyl {2-[(tert-butoxycarbonyl)amino]-3-(dimethylamino)-3-oxopropyl}carbamate (5.5 g, 15 mmol) in methanol (100 mL) was added palladium on carbon (0.55 g, 10% w/w). The reaction mixture was stirred under a hydrogen (50 psi) atmosphere at 50° C. After 4 hours, the reaction mixture was filtered and concentrated under reduced pressure to afford 3-amino-N2-(tert-butoxycarbonyl)-N,N-dimethylalaninamide. MS ESI calc'd. for C10H22N3O3 [M+H]+ 232. found 232. 1H NMR (400 MHz, CD3OD) δ 4.59-4.46 (m, 1H), 2.91 (s, 3H), 2.86 (s, 3H), 2.75-2.72 (m, 1H), 2.71-2.69 (m, 1H) 1.43 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([NH2:16])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC1CCCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H]1CCCN(Cc2ccccc2)C1

Procedure:
After the reaction liquid had been adjusted to a pH of 13 by the addition of 5 N aqueous solution of sodium hydroxide, N-benzyl-3-aminopiperidine was extracted with 1 L of toluene, and was then further extracted from the aqueous phase with 1 L of toluene. After the solvent had been distilled under reduced pressure away from a combination of the organic phases thus obtained, (R)—N-benzyl-3-aminopiperidine was purified by distillation. Thus, 17.7 g of (R)—N-benzyl-3-aminopiperidine were obtained in the form of colorless oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]#[C:23][Si](C)(C)C)[CH:19]=[CH:18][N:17]=1.CCN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:23]#[C:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(C#Cc2ccnc(Cl)c2)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
5-Bromo-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 1) (280 mg, 0.92 mmol) was dissolved in THF (20 ml). 2-Chloro-4-trimethylsilanylethynyl-pyridine [CAS 499193-57-6] (222 mg, 1.06 mmol, 1.15 equiv.), Et3N (1.28 ml, 9.2 mmol, 10 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (19 mg, 28 μmol, 0.03 equiv.) and copper(I)iodide (5 mg, 28 μmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (970 μl, 0.97 mmol, 1.05 equiv.) was added dropwise over a period of 20 minutes at 70° C. The reaction mixture was stirred for 2 hours at 70° C. and evaporated in presence of Isolute® sorbent to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column eluting with heptane:ethyl acetate 100:0→0:100. The desired 5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid tert-butylamide (210 mg, 73% yield) was obtained as a white solid, MS: m/e=314.4/316.4 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](N3C=C(C4C=CC=CC=4O)N=C3CC(C)C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S([O-])(=O)(=O)C>CN(C=O)C.O>[C:7]1([O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:30][CH:29]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)Cc1nc(-c2ccccc2O)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C

Procedure:
{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (2 mmol) was added to a solution of Cs2CO3 (10 eq., 20 mmol) in anhydrous DMF (5 ml). This was followed by addition of the mesylate obtained above and the reaction mixture was heated to 90° C. for 2-3 h. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired phenyl ether.
Reaction SMILES: C([CH:3]([C:22]([OH:24])=[O:23])[N:4]([CH2:15][P:16]([S:20][CH3:21])([S:18][CH3:19])=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[CH3:26]COCC>C(O)(=O)C>[CH2:5]([N:4]([CH2:15][P:16]([S:20][CH3:21])([S:18][CH3:19])=[S:17])[CH2:3][C:22]([OH:24])=[O:23])[CH3:26]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(=S)(SC)SC)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(SC)SC

Procedure:
Ethyl-N-[bis(methylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (5.9 g.) was dissolved in 11 ml. of 35% hydrobromic acid in acetic acid and stirred for one hour. Ether was added to the reaction solution which precipitated ethyl-N-[bis(methylthio)phosphinothioylmethyl]glycine hydrobromide salt as an oily liquid. This oil was washed three more times with additional ether. The material was suspended in benzene and treated with propylene oxide which effected almost complete solution. The solution was then concentrated to an oil at 0.5 torr. The oil thus recovered was chromatographed on 25 g. of silica gel employing diethyl ether as the eluant to yield ethyl-N-[bis(methylthio)phosphinothioylmethyl]glycine (1.46 g.) as an oil, ND25 =1.6002.
Reaction SMILES: [CH2:1]([N:8]1[C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[C:17]([C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:33][CH3:34])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:40](N1CCCCC1)=[O:41]>C(OCC)C.O1CCCC1>[CH2:1]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:33][CH3:34])=[C:13]([CH:40]=[O:41])[C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[C:24]([CH3:32])([CH3:31])[O:25][SiH2:26][C:27]([CH3:28])([CH3:29])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2Cc1ccccc1
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1C=O)Sc1c(ccc(OC)c1C(C)(C)O[SiH2]C(C)(C)C)N2Cc1ccccc1

Procedure:
A solution of 4.93 g (10.0 mmol) of 10-benzyl-4-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-phenothiazine in 50 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 7.5 ml of n-butyllithium solution (1.6M in hexane) and 1.47 g (13.0 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1.c. The 10-benzyl-3,7-dimethoxy-6-(tert.-butyl-dimethyl-silanyloxymethyl)phenothiazine-4-carbaldehyde obtained was dissolved in 50 ml of tetrahydrofuran and reduced with 10.0 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.8.b. The reaction mixture was worked up and chromatographed analogously to that described in 4.1.1.ea. After drying in a high vacuum 3.72 g (71.9%) of 10-benzyl-6-(tert.-butyl-dimethyl-silanyloxymethyl)-3,7-dimethoxy-phenothiazin-4-yl-methanol were obtained as an amorphous white solid. MS:
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH2:15])[CH2:5][CH2:4]1)[CH3:2].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)C.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)C.[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][C:57]=1[CH:58]=O)[N:54]([CH3:60])[C:53](=[O:61])[CH2:52][CH2:51]2>>[CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH:15][CH2:58][C:57]2[CH:56]=[C:55]3[C:50]([CH2:51][CH2:52][C:53](=[O:61])[N:54]3[CH3:60])=[CH:49][C:48]=2[O:47][CH3:46])[CH2:5][CH2:4]1)[CH3:2]
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Reactant: CCC1CCC(N)C(c2ccccc2)N1
Agent: CC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCC1CCC(NCc2cc3c(cc2OC)CCC(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-ethyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-ethyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-ethyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde.