Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl.[CH3:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[NH2:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:21]([NH:22][C:14](=[O:16])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:6]=1)([CH3:24])[C:20]([O:19][CH3:18])=[O:25]
Reactant: Cc1ccc(C(=O)O)nc1OCC(F)(F)F
Reactant: COC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C)c(OCC(F)(F)F)n1
Yield: 123.9 %

Procedure:
A solution of 5-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (30 mg, 128 μmol), 2-methyl-alanine methyl ester hydrochloride (23.5 mg, 153 μmol), HATU (CAN 148893-10-1, 97.0 mg, 255 μmol) and DIEA (82.4 mg, 109 μl, 638 μmol) in DMF was stirred at ambient temperature for 72 h. The crude reaction mixture was concentrated in vacuo to give 53 mg of a yellow solid. This solid was purified by preparative TLC (silica gel, 2.0 mm, 1:1 heptane/i-PrOAc) and eluted from the silica gel with i-PrOAc. Filtration over speedex and evaporation under reduced pressure provided the title compound (10 mg, 23%) as colorless liquid, MS (EI): m/e=335.2 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:18])[C:16]#[N:17])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[CH3:6].Cl.[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[CH3:21]>ClC1C=CC=CC=1>[CH:5]([C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:18])[C:16]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:20]([CH2:22][CH3:23])[CH3:21])=[CH:25][CH:26]=2)=[NH:17])=[CH:13][CH:14]=1)([CH2:7][CH3:8])[CH3:6]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CCC(C)c1ccc(N(C)C#N)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCC(C)c1ccc(NC(=N)N(C)c2ccc(C(C)CC)cc2)cc1
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Aluminum chloride (0.42 g, 3.1 mmol) was added to a stirred solution of N-4-sec-butylphenyl-N-methyl cyanamide (0.534 g, 2.84 mmol) in chlorobenzene (15 mL) at 145° C. After 10 minutes 4-sec-butylphenyl amine hydrochloride (0.474 g, 2.56 mmol, prepared from 4-sec-butyl aniline and 1.0 M HCl-ether) was added and continued reflux. After 2 hours, the reaction mixture was evaporated and the product was purified by flash chromatography to afford the title compound (0.45 g, 65%) as a syrup. TLC: Rf=0.22 (CH2Cl2:CH3OH; 10:1); 1H NMR (CD3OD): δ 7.27 (d, 4H, J=8.18 Hz, ArH), 7.20 (d, 4H, J=8.36 Hz, ArH), 3.46 (s, 3H, —NCH3), 2.69-2.58 (m, 2H, 2×—CH), 1.68-1.57 (m, 4H, 2×—CH2)1, 1.25 (d, 6H, 2×—CH3), 0.85 (t, 6H, 2×—CH3); HRMS: 337.2484 (337.2528 Calcd. for C22H31N3); HPLC: (CH3CN:H2O; 50:50 with 0.1% TFA): 98% pure.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[Br:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36]O>C(Cl)Cl>[Br:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36][I:25]
Reactant: OCCc1ccc(F)cc1Br
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(CCI)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A solution of Ph3P (2.57 g, 9.81 mmol) and imidazole (0.668 g, 9.81 mmol) in DCM (50 mL) was cooled to 0° C. Added to this was iodine (2.489 g, 9.81 mmol) and the resulting mixture was stirred at 0° C. for 30 min. 2-(2-Bromo-4-fluorophenyl)ethanol (1.79 g, 8.17 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temp. After 16 h, the mixture was filtered washing the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give 2-bromo-4-fluoro-1-(2-iodoethyl)benzene (2.4 g, 7.30 mmol, 89% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.33 (dd, J=8.2, 2.7 Hz, 1H), 7.25 (dd, J=8.5, 5.8 Hz, 1H), 7.02 (td, J=8.2, 2.6 Hz, 1H), 3.41-3.35 (m, 2H), 3.32-3.26 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 64.6 %

Procedure:
3-fluoroaniline (40 g) was dissolved in MeOH and the solution was cooled to 0° C. Tert-butyl 4-oxo-1-piperidinecarboxylate (79 g, 1.1 eq), acetic acid (26.8 ml, 1.3 eq) and sodium cyanoborohydride (29 g, 1.3 eq, portionwise) were added successively to the solution. The reaction mixture was stirred at room temperature until completion. The reaction mixture was then cooled to 0° C. and an aqueous solution of NaOH (20%) was poured into the mixture (pH˜10). The precipitate was filtered off, washed with water, dried and recrystallised from iPrOH to give tert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate 1 (68.5 g).
Reaction SMILES: [C:1]1([C:11]#[C:12][CH2:13][OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:11]#[C:12][CH:13]=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCC#Cc1cccc2ccccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=CC#Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of 3-naphthalen-1-yl-prop-2-yn-1-ol (3.51 g, 19.26 mmol) in dichloromethane (60 mL) and tetrapropylammonium perruthenate (0.14 g, 0.39 mmol, 2 mol %) was stirred at 0° C. under an atmosphere of nitrogen. N-methylmorpholin-N-oxide (4.06 g, 34.67 mmol, 1.8 eq.) was divided into 4 portions and the first portion (1.01 g, 8.67 mmol) was added to the reaction mixture and the resulting black mixture was stirred at room temperature for an hour. The remaining portions were added sequentially at hourly intervals and the mixture was left to stir for a further 19 hours. The TLC of the reaction mixture indicated that the starting material had been consumed and the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50 mL) and the reaction mixture was extracted with dichloromethane (3×50 mL), dried over sodium sulphate and concentrated in vacuo to afford a black residue. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 30%:70%) to afford the desired compound as a yellow oil (2.85 g, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 7.49-7.65 (4H, m, ArH), 7.89 (1H, d, J 8.0 Hz, ArH), 7.99-8.01 (1H, d, J 8.0 Hz, ArH), 8.32-8.34 (1H, d, J 8.4 Hz, ArH), 9.57 (1H, s, CHO).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[Br:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:10][CH2:11][CH2:12][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: NCc1cccc(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cccc(CNCCBr)c1

Procedure:
Combine 3-fluorobenzylamine (5.0 g, 0.0400 mol), fused sodium acetate (3.28 g, 0.0400 mol) and 1,2-dibromoethane (7.51 g, 0.0400 mol) and reflux for several hours. Pour the mixture into water and add sodium carbonate to create a basic pH. Remove the unreacted 1,2-dibromoethane by distillation. Extract the left-over residue with ether and evaporate to obtain the final, desired compound. The compound can form the hydrochloride salt.
Reaction SMILES: [ClH:1].O=[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[CH2:21]4)[CH2:16][CH2:15]3)[CH:11]=2)[N:6]=[CH:5][NH:4]1>C(#N)C>[ClH:1].[Cl:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[CH2:21]4)[CH2:16][CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1
Agent: Cl
Solvent: CC#N
Product: COc1cc2ncnc(Cl)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
210 g of 3,4-dihydro-4-oxo-6-[trans-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexyloxy]-7-methoxy-quinazoline hydrochloride [(V) HCl] in 1680 ml acetonitrile are refluxed and 840 ml of solvent are distilled off (elimination of traces of water). 221.4 g triphenylphosphine in 840 ml dioxane are added. 119.4 g of N-chlorosuccinimide in 600 ml acetonitrile are added. 260 ml acetonitrile are added. The mixture is stirred for 45 min at 80° C. and then cooled to 30° C. 8.94 ml of water and 420 ml dioxane are added. The precipitate is filtered off under protective gas and washed with 1200 ml THF. The product is precipitated as the hydrochloride and is processed further without drying. A small amount was dried and the yield can be calculated as approx. 210 g in relation thereto.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:17]([C:16]1[CH:15]=[C:14]([CH:21]=[CH:20][CH:19]=1)[O:13][C:4]1[CH:3]=[C:2]([CH3:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])=[O:18]
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)c1
Yield: 35.4 %

Procedure:
4-Methyl-2-nitrobenzonitrile (0.50 g, 3.1 mmol), 3-hydroxybenzaldehyde (0.38 g, 3.1 mmol) and cesium carbonate (1.00 g, 3.1 mmol) were heated with stirring in dry DMF (5 mL) at 80° C. for 28 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 0.1N sodium hydroxide solution (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-phenoxy)-4-methyl-benzonitrile (0.26 g, 36%) as a brown resin, and was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 7 g of 5-aminopyridine-2-carboxylic acid methyl ester, 8.9 g of 3,4-dichlorobenzaldehyde, and 40 ml benzene are refluxed for 29 hours on a water-separating trap. The initial suspension becomes a clear solution, which is evaporated. The solid residue is triturated with diethyl ether and recrystallized from acetonitrile, to yield the 5-(3,4-dichlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 202°-207°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O>[N+:1]([C:7]1[CH:6]=[C:5]([N:11]2[CH:15]=[N:14][N:13]=[C:12]2[C:16]([F:17])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=1)([O-:4])=[O:2]
Reactant: FC(F)(F)c1nncn1-c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(-n2cnnc2C(F)(F)F)c1
Yield: 63.9 %

Procedure:
Fuming nitric acid (0.5 g) was added to 4-phenyl-3-trifluoromethyl-1,2,4-triazole (1.06 g) (see Example 1) in concentrated sulphuric acid (15 ml) at 5°-10° and then slowly heated to 85° for 1 hr. The cooled acid solution was poured onto ice to give 4-(3-nitrophenyl)-3-trifluoromethyl-1,2,4-triazole (0.82 g, 63.4%) m.p. 142° (from benzene). Found: C, 41.70%; H, 2.13%; F, 22.1%; N, 21.43%. C9H5F3N4O2 requires: C, 41.87%; H, 1.95%; F,22.1%; N, 21.70%). High resolution nmr spectroscopy indicated substitution in the m-position of the phenyl ring. m/e, 259.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])=[C:4]([F:11])[S:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].[CH2:23](O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:12]2[C:13](=[O:22])[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]2=[O:21])=[C:4]([F:11])[S:5][C:6]=1[CH2:7][C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: CCO
Reactant: O=C(O)Cc1sc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1sc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1Cl

Procedure:
To a solution of 2-(4-chloro-2-fluoro-5-carboxymethylthiophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.2 g) and ethanol (1.0 g) in toluene (20 ml), there was added a small amount of p-toluenesulfonic acid, and the mixture was refluxed for 3 hours. Water was added to the reaction mixture. The toluene layer was separated, dried and concentrated. The residue was purified by silica gel chromatography to give 0.1 g of 2-(4-chloro-2-fluoro-5-ethoxycarbonylmethylthiophenyl-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione. nD18 1.5670.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH3:18])[CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H](C(=O)Nc1cccc(OCc2ccccc2)c1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)Nc1cccc(O)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 107 %

Procedure:
To 10% palladium-carbon (100 mg), a solution of (S)-tert-butyl (1-((3-(benzyloxy)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (E15, 166 mg) in methanol (4 mL) and tetrahydrofuran (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 5 hours and 30 minutes under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain (S)-tert-butyl (1-((3-hydroxyphenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (E16, 136 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 95 %

Procedure:
As described for example 8e, 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol), was converted, using 1-fluoro-4-nitrobenzene instead of 4-fluorobenzotrifluoride, to the title compound (100 mg, 95%) which was obtained as a yellow solid. MS: m/e=365.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:37]4[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCN(CCc2cccc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]acetaldehyde (D78) (160 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (189 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D89) (216 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C30H37ClN2O3S requires 540. found 541.2 (M+H+).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[ClH:15].C(N(CC)CC)C.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44](=O)[NH:43][N:42]=2)=[CH:36][CH:35]=1>ClCCl>[ClH:15].[ClH:15].[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:41]([CH2:40][C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)=[N:42][N:43]=2)=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 210 °C
Reaction time: 4.5 h

Procedure:
In the manner described in Example 45, a mixture of 1.80 g (12.68 mmol) phosphorus pentoxide, 1.73 g (12.6 mmol) triethylamine hydrochloride, 1.9 ml (12.5 mmol) 4-tert-butylaniline, and 1 g (4.2 mmol) 4-(4-pyridylmethyl)-1(2H)-phthalazinone is stirred for 4.5 h at 210° C. The frozen melt is then dissolved in dichloromethane using an ultrasonic bath, filtered off from undissolved components, and the filtrate evaporated in the RE. The oil-like residue is distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia, and the organic phase dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue is then stirred with 10 ml acetonitrile, filtered off from some non-transformed 4-(4-pyridylmethyl)-1(2H)-phthalazinone, and the filtrate evaporated under vacuum. Flash chromatography of the residue on silica gel with a particle size of 0.04-0.06 mm using a toluene/acetone mixture (7:3) yields a resin (free base of the title compound), which is dissolved in a mixture of 4 ml methanol and 1.5 ml of 3 N methanolic HCl. After evaporation under vacuum, recrystallization of the residue from methanol/ether, drying under HV (6 h, 80° C.), and equilibration for 16 h at 200° C. and in room atmosphere, title compound is obtained with a water content of 4.47%; m.p. 196-200° C.; ESI-MS: (M+H)+=369.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:5]1[CH2:7][N:6]1[CH2:8][C:9]1[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=1)#[N:4]>CC(C)=O>[C:3]([CH:5]1[CH2:7][N:6]1[CH2:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)#[N:4]
Reactant: COC(=O)c1ccc(CN2CC2C#N)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: N#CC1CN1Cc1ccc(C(=O)O)s1
Yield: 61 %

Procedure:
95 ml. 0.1 N Aqueous sodium hydroxide solution are added dropwise, with stirring, to 2.1 g. 2-cyano-1-(5-methoxycarbonyl-2-thenyl)-aziridine (see Example 13a) in 21 ml. acetone. When no more ester can be detected by thin layer chromatography, the reaction mixture is evaporated in a vacuum, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The evaporation residue is crystallized with diethyl ether. There is obtained 1.2 g (61% of theory) 2-cyano-1-(5-carboxy-2-thenyl)-aziridine; m.p. 108°-111° C. The sodium salt melts with decomposition at 238°-243° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[C:17]([CH2:24]I)[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]2[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1.O>CN(C)C=O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH2:24][C:17]1[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[C:14]2[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=2)[N:18]=1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2ccccc2=O)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
Oily sodium hydride (60%, 0.117 g) was added to a solution of 2-hydroxypyridine (0.277 g) in N,N-dimethylformamide (DMF)(10 ml), and the mixture was stirred at room temperature for 15 minutes. To this solution was added ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylate (1.2 g). The mixture was stirred at room temperature for 8 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (10/1, v/v) gave ethyl 2-(1,2-dihydro-2-oxopyridine-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.64 g, 57%) which was then recrystallized from ethanol. Colorless prisms. mp. 154°-156° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:5]1[CH:6]=[CH:7][C:8]([C:16](O)=[O:17])=[N:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[NH2:26][C:27]([CH2:34][CH3:35])([CH2:32][CH3:33])[C:28]([NH:30][CH3:31])=[O:29]>>[CH2:32]([C:27]([NH:26][C:16]([C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:3][C:2]([F:1])([F:25])[F:24])[CH2:19][C:20]([F:22])([F:21])[F:23])=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:17])([C:28](=[O:29])[NH:30][CH3:31])[CH2:34][CH3:35])[CH3:33]
Reactant: O=C(O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 162 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=499.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].[NH3:14]>C(Cl)Cl>[CH3:1][S:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:14])(=[O:12])=[O:11]
Reactant: N
Reactant: CSCc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CSCc1ccccc1S(N)(=O)=O
Reaction time: 2 h

Procedure:
To a solution of 26 g (50% pure, 55 mmol) of o-methylthiomethylbenzenesulfonyl chloride in 250 ml of methylene chloride was added 4.5 ml of anhydrous ammonia at 0°-5° over 1 hour. Stirring was continued at 0°-5° C. for 2 hours. The solid precipitate was filtered off and the filtrate was evaporated to dryness to afford 24.8 g of orange residue. The crude product was triturated in ether, resulting in light pink crystals: m.p. 119°-124° C.