Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(O)C.CCCCCC>[O:15]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:5])[N:7]1[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19]
Reactant: c1ccccc1
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CC(C)CC(C(=O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Thionyl chloride (34.8 ml, 480 mmol) was added to a mixture of 2-(1,3-dioxo-2-azaindane-2-yl)-4-methylpentanoic acid (83.61 g, 320 mmol) and benzene (320 ml). The resulting mixture was heated under reflux for 2 hours. The solvent and excess thionyl chloride were removed by distillation under reduced pressure, followed by addition of benzene (320 ml). The benzene was removed and fresh benzene (480 ml) was added to form a solution. Anhydrous aluminum chloride (106.7 g, 800 mmol) was added immediately to the solution and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water (700 ml). The aqueous layer was extracted with benzene (200 ml). After being washed first with water and then with an aqueous sodium bicarbonate solution and with brine, the combined organic layer was dried over sodium sulfate and then evaporated under reduced pressure. The residue was treated with ethanol to obtain crystals. The crystals were dissolved with heating in ethanol (80 ml) and added with hexane (160 ml). Precipitated crystals were collected by filtration and washed first with a 1:2 mixed solution (240 ml) of ethanol and hexane and then with hexane. The crystals were dried in air to obtain 74.6 g of the intended compound as white crystals (yield: 73%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[S:5][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:7][N:8]=1.I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I>CN(C=O)C>[Cl:3][C:4]1[S:5][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:12]3[CH2:13][CH2:14][N:10]([CH2:9][C:6]4[S:5][C:4]([Cl:3])=[N:8][CH:7]=4)[C:11]3=[N:15][N+:16]([O-:18])=[O:17])[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:7][N:8]=1
Reactant: O=[N+]([O-])N=C1NCCN1Cc1cnc(Cl)s1
Reactant: ICCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])N=C1N(CCCCCCN2CCN(Cc3cnc(Cl)s3)C2=N[N+](=O)[O-])CCN1Cc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (60%, 0.48 g, 12 mmol) in 20 ml of DMF was prepared. 1-(2-Chloro-5-thiazolylmethyl)-2-nitroiminoimidazolidine (2.61 g, 10 mmol) was added to this suspension. The resulting mixture was then stirred for 1 hour at room temperature. 1,6-Diiodohexane (1.64 g, 5 mmol) was added dropwise to this reaction mixture over the course of 30 minutes while cooling the reaction mixture with ice. Following completion of dropping, the mixture was stirred for 4 hours at room temperature. The DMF was distilled off from the reaction mixture under reduced pressure. The residue was then shaken with a mixture of water and chloroform. After separating the chloroform layer and drying, the solvent was distilled off under reduced pressure. The semi-solid residue was subjected to silica gel column chromatography with a mixture (15:1 (v/v)) of ethyl acetate and ethanol as the eluate. The crude product was recrystallized from methanol. The yield of crystalline product was 0.22 g (70%), and the melting point was 204 to 206° C. The results of elementary analysis and NMR analysis are shown below.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH:10]([CH3:14])C(O)=O)=[O:8])=[O:4].C(Cl)(=O)[C:16](Cl)=[O:17].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22].C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[C:7]([O:9][CH2:10][CH2:14][C:16](=[O:17])[N:26]([CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)OC(C)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)CCOC(=O)/C=C/C(=O)OC
Yield: 33.3 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]propanoic acid (24) (0.50 g, 2.47 mmol) was activated with oxalyl chloride (0.25 mL, 0.35 g, 2.71 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with N-benzyl glycine ethyl ester (Bn-Gly-OEt) (0.56 g, 2.90 mmol) in DCM and diisopropylethylamine (DIEA) (0.506 mL, 0.376 g, 2.90 mmol) in the presence of a catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.31 g (33% yield) of the title compound (37) as a white solid. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 7.37-7.17 (m, 5H), 6.88-6.77 (m, 2H), 5.49 (q, J=6.4 Hz, 0.75H), 5.33 (q, J=6.4 Hz, 0.25H), 4.7-4.27 (m, 3H), 4.16-4.13 (m, 2H), 3.83-3.63 (m, 4H), 1.53 (d, J=6.8 Hz, 3H), 1.21 (t, J=4.0 Hz, 3H). MS (ESI): m/z 378.10 (M+H)+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[CH2:9][O:10][C:11](=[O:22])[C:12](=[N+]=[N-])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(OCC)(OCC)OCC>C1(C)C=CC=CC=1.[Cu]I>[C:16]([O:15][C:13]([C@:12]12[C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@H:8]1[CH2:9][O:10][C:11]2=[O:22])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)OC/C=C\c1ccccc1
Agent: [Cu]I
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@@]12C(=O)OC[C@@H]1[C@@H]2c1ccccc1
Temperature: 130 °C

Procedure:
To the 2-diazomalonic acid t-butyl ester (Z)-3-phenyl-allyl ester (16 g, 54 mmol) above were added triethyl phosphite (0.090 g, 0.54 mmol) and copper (I) iodide (0.10 g, 0.54 mmol) in toluene (490 mL). After heating at 130° C. for 5 hours, the solid was filtered off and the filtrate was concentrated. The reaction mixture was purified by column chromatography using dichloromethane as an eluent. Purification afforded 5.2 g of the desired diastereomer and 2.8 g of the other diastereomer.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[NH:17][C:16](=[O:18])[C:15]2=[C:19]([CH3:25])[N:20]=[C:21]([CH2:22][CH2:23][CH3:24])[N:14]2[N:13]=1)[CH3:2].[Cl:26][S:27](O)(=[O:29])=[O:28]>>[CH2:1]([O:3][C:4]1[C:5]([C:12]2[NH:17][C:16](=[O:18])[C:15]3=[C:19]([CH3:25])[N:20]=[C:21]([CH2:22][CH2:23][CH3:24])[N:14]3[N:13]=2)=[CH:6][C:7]([S:27]([Cl:26])(=[O:29])=[O:28])=[C:8]([O:10][CH3:11])[CH:9]=1)[CH3:2]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3ccc(OC)cc3OCC)nn12
Reactant: O=S(=O)(O)Cl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)c(OC)cc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 0.31 g (0.9 mmol) of 2-(2-ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one are added slowly to 0.54 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 0.355 g (89%) of a colourless foam. Rf=0.50 (dichloromethane/methanol=20:1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCC(C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(N)c2)cc1
Yield: 86.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-(2-phenylpropyl)amine (3.17 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.7 g) and sodium borohydride (1.18 g) were reacted, to afford the title compound (2.52 g) as a clear purple oil.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][C:23]([O:25][C:26](C)(C)[CH3:27])=[O:24])[CH:11]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1)=[O:5])C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][C:4]([OH:5])=[O:3])[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCc1cc(CCC(=O)OC(C)(C)C)cc(Oc2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(CCC(=O)O)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
A solution of t-butyl 3-[3-(2-ethoxycarbonylethyl)-5-(3-pyridyloxy)phenyl]propanoate (Preparation 29; 7.8 g) in dichloromethane (100 ml) was treated with trifluoroacetic acid (20 ml) and the resulting solution stirred at room temperature for 20 hours and then evaporated under vacuum. The residue was azeotroped twice with toluene, and then ether (ca 100 ml) and pyridine (ca 10 ml) were added sequentially. This mixture was washed with water and then the combined aqueous washings extracted with ethyl acetate. The organic solutions were combined, washed with water, dried (MgSO4) and evaporated under vacuum to provide an oil, which crystallised on trituration with an ether: hexane mixture to give the title compound (6.56 g), m.p. 85°-87° C. Found: C,66.67; H,6.04; N,3.90. C19H21NO5 requires C,66.46; H,6.16; N,4.08%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:16][CH2:17][O:18][CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([NH2:15])=[S:14].[CH3:20][I:21]>CC(C)=O>[IH:21].[CH3:20][S:14][C:13](=[NH:15])[NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:16][CH2:17][O:18][CH3:19]
Reactant: CI
Reactant: COCCN(CCOC)c1ccccc1NC(N)=S
Solvent: CC(C)=O
Product: COCCN(CCOC)c1ccccc1NC(=N)SC
Product: I
Temperature: 40 °C

Procedure:
A mixture of 1-((2-[bis(2-methyoxyethyl)amino]phenyl))thiourea (5 g), methyl iodide (1.4 ml) and acetone (25 ml) was heated at 40° C. for 2 hours. Removal of the solvent gave a residue which was triturated with ether to give 2-methyl-1-((2-[bis(2-methoxyethyl)amino]phenyl))-2-thiopseudourea hydroiodide (m.p. 111°-112° C.).
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([C:16]([F:17])([F:19])[F:18])[CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(-n2cncn2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-n2cncn2)cc1C(F)(F)F
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a solution of methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g) in methanol was added aqueous sodium hydroxide (1.50 g) at 20° C. The mixture was stirred for 4 hours, partially evaporated and extracted with ether. The aqueous layer was acidified (aqueous citric acid) and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate), and evaporated to give 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoic acid (3.32 g), NMR 8.25(1H), 8.34-8.42(3H), 10.00(s, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([N:28]3[C:32]([CH3:33])=[N:31][N:30]=[N:29]3)[CH:19]=2)[C@@H:11]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+].O>CS(C)=O>[N:1]([CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([N:28]3[C:32]([CH3:33])=[N:31][N:30]=[N:29]3)[CH:19]=2)[C@@H:11]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nnnn1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nnnn1-c1cc(CO[C@H]2CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
Sodium azide (14 mg, 0.21 mmol) was added to a solution of [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine (90 mg, 0.18 mmol) in dimethyl sulphoxide (3 ml) and the solution was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give [2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow oil (89 mg, 98%) 1H (CDCl3) δ 7.54 (2H, s), 7.43-7.08 (6H, m), 4.62 (1H, d, J=13.2 Hz), 4.18 (1H, d, J=13.2 Hz), 3.92 (2H, s), 3.61-3.30 (4H, m), 3.02 (1H, m), 2.69 (1H, m), 2.55 (3H, s), 2.14 (2H, m), and 1.62 (2H, m). m/z 511 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][C:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Nc1ccc(Oc2cccnc2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 500 mg (2.81 mmol) of 4-(pyridin-3-yloxy)phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to yield 7-fluoro-6-methoxy-4-[4-(pyridin-3-yloxy)-phenylamino]-quinoline-3-carbonitrile as an off-white solid, mp 235-236° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(OC)cc2)c1C(=O)OC
Yield: 116.4 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol) in acetone (45 mL) and potassium carbonate (2.2 g, 15.7 mmol), was added 1-bromomethyl-4-methoxy-benzene (0.79 mL, 5.5 mmol). The mixture was refluxed for six hours. The solvent was evaporated in vacuo, and the residue was partitioned between water (50 mL) and ethyl acetate (80 mL). The organic layer was washed with water (2×50 mL), dried, concentrated in vacuo, and purified by flash column chromatography (Silica Gel, EtOAc/Hexane, 0% gradient to 100% 30 min) to give 3-(4-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.0 g, 115% crude yield). The product was used in the next step without further purification.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])(C)C.[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.[C:24](O)(=O)[CH2:25][C:26](CC(O)=O)(C(O)=O)O>CS(C)=O.O>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([NH:13][S:10]([C:5]2[CH:4]=[CH:9][C:8]([CH:25]([CH3:26])[CH3:24])=[CH:7][CH:6]=2)(=[O:11])=[O:12])[CH:22]=1
Reactant: CC(C)c1ccccc1S(N)(=O)=O
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
996 mg (5.0 mmol) of isopropylbenzenesulfonamide were dissolved in 20 ml of dimethyl sulfoxide, after which 288 mg (6.0 mmol) of 50% sodium hydride were added and the mixture was stirred at room temperature for 30 minutes. 819 mg (5.5 mmol) of 4,6-dichloropyrimidine were then added and the reaction mixture was stirred overnight at room temperature. Subsequently, the mixture was heated at 90° C. for 3 hours and, after that, stirred at 120° C., in a microwave oven, for 30 minutes. After the reaction mixture had cooled down to room temperature, it was diluted with 150 ml of water, neutralized with citric acid and extracted three times with diethyl ether. The residue, which was obtained after drying with sodium sulfate and after removing the solvent, was dissolved in 100 ml of diethyl ether and extracted with an aqueous solution of sodium hydrogen carbonate. The aqueous phase was acidified and extracted with diethyl ether. The organic phase was dried, filtered and evaporated down to dryness, with 440 mg (28% of theory) of the title compound being obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][CH2:32][OH:33])=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCNCCO
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(CCO)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 2-ethylamino-ethanol
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([F:42])([F:41])[F:30])[CH:28]=[C:27]([F:29])[CH:26]=3)[N:7]=2)=[CH:20][CH:21]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=c1n(Cc2cc(F)cc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 59 mg (0.12 mmol) of the compound from Example 103A were reacted with 36 mg (0.18 mmol) of 2-(trifluoromethyl)phenylboronic acid. This gave 43 mg (64% of theory) of the target compound.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH3:34])[CH:22]=1)=O)([CH3:3])[CH3:2].Cl.[CH3:36][O:37][NH2:38]>>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH3:34])[CH:22]=1)=[N:38][O:37][CH3:36])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)cc1C
Agent: Cl
Product: CCOC(=O)COc1ccc(C(CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)=NOC)cc1C

Procedure:
The titled compound was prepared from ethyl 4-[3-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-2-methylphenoxyacetate [Example 15 (2)] (70 mg, 0.14 mmol) and methoxyamine hydrochloride (13 mg, 0.16 mmol) in a procedure similar to that of Example 13 (1) as a yellow oil (74 mg, yield>99%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][N:4]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2=[N:24][N:25]=[C:26]([C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)[N:16]2[N:15]=1>>[CH3:11][C:9]([NH2:12])([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3=[N:24][N:25]=[C:26]([C:27]4[CH:31]=[C:30]([CH3:32])[O:29][N:28]=4)[N:16]3[N:15]=2)=[N:4][CH:5]=1)[CH3:10]
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: CC(C)(N)c1ccc(CO)nc1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C(C)(C)N)cn4)nn23)no1

Procedure:
The reaction was carried out as described in Example 1, Step 4 using 1-[2-(hydroxymethyl)pyridin-5-yl](1-methyl)ethylamine (330 mg, 1.98 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine to give after column chromatography on silica, eluting with 4% MeOH/CH2Cl2 containing 1% NH3 solution, the title compound (504 mg, 61%) which was recrystallised from CH2Cl2/hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH2:21][O:22]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:19])([F:18])[F:20])[N:16]=[C:10]2[CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1CO
Reaction time: 29 h

Procedure:
To a solution of 733 mg (1.8 mmol) of 7-N-(tert-butoxycarbonyl)-8-[(benzyloxy)methyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine in 8.0 mL of ethanol was added 400 mg of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen for 29 h. TLC analysis indicated that starting material was present. Thus 400 mg of 10% palladium on carbon was added and the mixture shaken on a Parr apparatus under 42 psi hydrogen for 12 h. The reaction mixture was filtered through Celite and concentrated. Flash chromatography (silica gel, 7% to 50% ethyl acetate/hexane gradient) gave the title compound as a white solid. LC/MS 267 (M+1-tBu).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>C(#N)C>[Br-:1].[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][N+:16]=1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccn1
Reactant: BrCCCCCCCCc1ccccc1
Solvent: CC#N
Product: Cc1cccc[n+]1CCCCCCCCc1ccccc1
Product: [Br-]
Yield: 70 %

Procedure:
(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 2-picoline (3 mmol) in acetonitrile, and the solution mixture was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (70%). 1HNMR (300 MHz, CDCl3, ppm) 9.74 (d, 1H), 8.35 (m, 1H), 7.96 (m, 1H), 7.86 (d, 1H), 7.15-7.25 (m, 4H), 4.92 (t, 2H), 2.95 (s, 3H), 1.88-1.98 (m, 2H), 1.54-1.64 (m, 2H), 1.39-1.49 (m, 2H), 1.25-1.38 (br, 6H).