Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12.[N:17]1([CH2:22][CH2:23][O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:11]1([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[N:29]3[CH2:30][CH2:31][CH:26]([CH2:25][O:24][CH2:23][CH2:22][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:27][CH2:28]3)[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: Clc1ccnc2scc(-c3ccccc3)c12
Product: c1ccc(-c2csc3nccc(N4CCC(COCCN5CCCC5)CC4)c23)cc1
Temperature: 170 °C
Yield: 10.8 %

Procedure:
4-Chloro-3-phenyl-thieno[2,3-b]pyridine (150 mg, 0.462 mmol) and 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (150 mg, 0.706 mmol) were combined and heated in a Reactivial at 170° C. overnight. The reaction mixture was allowed to cool to room temperature and purified by basic prep HPLC to afford 3-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-b]pyridine (21 mg). LCMS [M+H]=422.2
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([C:71]([F:74])([F:73])[F:72])=[CH:67][N:66]=2)[CH2:60][CH2:59]1>CN(C)C=O.ClCCl.O1CCCC1>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]([N:58]3[CH2:59][CH2:60][CH:61]([NH:64][C:65]4[CH:70]=[CH:69][C:68]([C:71]([F:72])([F:74])[F:73])=[CH:67][N:66]=4)[CH2:62][CH2:63]3)=[O:20])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(NC2CCNCC2)nc1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (18 μL; 0.10 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol, prepared in accordance with Example 50) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution piperidin-4-yl-(5-trifluoromethyl-pyridin-2-yl)-amine hydrochloride (14 mg; 0.05 mmol) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 150 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (14 mg; 0.03 mmol). The structure was confirmed using Protocol I-B. Calculated mass=544; observed mass=544; HPLC retention time=4.47 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[C:14]1([N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=[C:2]([C:28]#[C:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3]2=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=c1c(C#Cc2ccccc2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 50 °C
Yield: 6.6 %

Procedure:
100 mg of 3-bromo-1-phenyl-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one, 55 mg of phenylacetylene, 1 mg of copper(I) iodide and 4 mg of dichlorobis(triphenylphosphine)palladium were added to a mixed solvent of 1.5 ml of triethylamine and 1 ml of dimethylformamide, and stirred at 50° C. in a nitrogen atmosphere for a night. The reaction mixture was distributed into the ethyl acetate and water layers. The organic layer was washed with water, dried and concentrated, and the residue was refined by silica gel chromatography (ethyl acetate/hexane-based solvent), to obtain 7 mg of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.O=S(Cl)Cl.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:16]2[CH2:18][CH2:17]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NC1CC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-2-methylbenzoic acid and SOCl2 was refluxed for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 30 mL CH2Cl2 and combined with cyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine,(2.05 g, 26.0 mmols). The solution was stirred for 18 hours and then diluted with EtOAc before being washed with 5% aqueous HCl, saturated NaHCO3, and saturated aqueous NaCl. The solution was dried (MgSO4) and concentrated under reduced pressure leaving the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16]([N:3]([CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[CH2:1][CH3:2])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCNCCN(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: CCN(CCN(C)C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of N′-ethyl-N,N-dimethylethane-1,2-diamine (0.62 mL, 4.4 mmol) in methylene chloride (10 mL) was added 6-chloropyridine-3-sulfonylchloride (0.85 g, 4 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) dropwise. The reaction mixture was stirred for 30 min at room temperature followed by the extraction with aqueous HCl (5%). The acidic water layer was alkalized with an aqueous saturated solution of NaHCO3 and extracted with methylene chloride. The organic phase was dried (Na2SO4) and evaporated in vacuo to give 0.7 gram (60% yield) of the title compound: MS (ES) m/z 292 (M++1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[N:32]([CH3:34])[CH:31]=[C:30]4[CH:35]=O)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+]>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[N:32]([CH3:34])[CH:31]=[C:30]4[CH2:35][NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CNCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Ethyl glycinate hydrochloride (698 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (396 mg) were added to a solution of NaOH (200 mg) in ethanol (10 mL). After stirring for 0.5 hour, ethanol was evaporated off and then Dichloromethane (40 mL) containing AcOH (0.5 mL) was added to the residue. NaBH(OAc)3 (1.06 g) was added to the above mixture. The reaction mixture was stirred at room temperature overnight and then terminated by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}glycinate (D77) (283 mg) as a yellow solid. δH (CDCl3, 400 MHz): 1.29 (3H, t), 1.46 (6H, d), 1.84 (1H, br s), 3.48 (2H, s), 3.74 (2H, s), 4.03 (3H, s), 4.21 (2H, q), 4.71-4.74 (1H, m), 7.03 (1H, s), 7.07 (1H, d), 7.22 (1H, t), 7.58 (1H, dd), 7.89 (1H, dd), 8.08 (1H, dd), 8.26 (1H, d). MS (ES): C25H27ClN4O4 requires 482; found 380.2 (M—NHCH2COOEt+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=O.O.[NH2:17][NH2:18]>CO>[NH:17]([C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=[O:2])[NH2:18]
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1cc(S)n2nc(C(=O)NN)nc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-methoxycarbonyl-7-mercapto5-methyl-s-triazolo[1,5-a]pyrimidine (10 g) in 200 ml of methanol was dropwise added hydrazine hydrate (110 ml). The mixture was stirred at room temperature for two hours, the insoluble matters were filtered off, and the solvent was removed by distillation from the filtrate. Water (100 ml) was added to the residue and the pH was adjusted to 4.0 with 1N hydrochloric acid. The formed crystals were collected by filtration and washed with 100 ml of water, then with 100 ml of methanol, affording 7.2 g of the objective compound as yellow crystals.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:34])[CH:25]=4)=[N:21][C:20]=3[CH3:35])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[F:34][C:26]1[CH:25]=[C:24]([C:22]2[S:23][C:19]([CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[CH:9][N:8]4[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=3)=[C:20]([CH3:35])[N:21]=2)[CH:29]=[CH:28][C:27]=1[C:30]([F:32])([F:31])[F:33]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2)sc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2)sc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {6-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid as off-white solid.
Reaction SMILES: C.Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.[Pd]>[C:3]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
In a miniautoclave, 85 mg of palladium on active charcoal (similar to Example 59, metal content 5%) are suspended in 20 ml of DMF. After 2 mmol of bromobenzene, 2 mmol of styrene, and 4 mmol of tetrabutylammonium acetate have been added, heating at 120° C. is performed with shaking. After 16 h, 267 mg of stilbene can be isolated from the reaction solution. This corresponds to a 74% conversion.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=1.Cl[Si](C)(C)C.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:13](=[O:15])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:31][CH:32]=1)([OH:38])=[O:37]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)COc1ccc2ccccc2c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccc2ccccc2c1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-Naphthoxy)acetic acid (8.5 g) is suspended in 160 mL methylene chloride and treated with 1,1'-carbonyldiimidazole (6.8 g) which is added in small portions. After stirring for 3 hrs at room temperature under a nitrogen atmosphere, the mixture is added dropwise to a previously prepared solution of alpha-amino-p-toluic acid (1.4 g), chlorotrimethylsilane (10 mL), and triethylamine (11 mL) in 250 mL methylene chloride at 0° C. The final mixture is stirred at room temperature under a nitrogen atmosphere overnight. The mixture is combined with 200 mL 1N HCl and shaken, after which the resultant precipitate is collected by suction filtration. The precipitate is recrystallized from methanol/2N HCl, m.p. 188°-189° C. as N-(4-carboxybenzyl)-(2-naphthoxy)acetamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([N:24]([CH:27]([CH3:29])[CH3:28])[CH2:25][CH3:26])(C)C.CS(C)=O>O>[C:9]1([CH3:10])[CH:8]=[CH:6][CH:5]=[CH:4][C:29]=1[CH:27]1[CH2:28][CH2:26][CH2:25][N:24]1[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N4CCCC4c4ccccc4C)n3)cc2s1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), 2-O— tolylpyrrolidine (0.053 g, 0.33 mmol) oxalate, diisopropylethylamine (0.20 ml, 1.2 mmol) in DMSO (1.0 g, 11 mmol) was heated under CEM microwave at 140° C., 130 W (Powermax® off) for 20 min. The resultant was diluted with 5 ml of water and filtered. The solid was dried to give a brown solid (0.065 g, 46%). MS (ESI pos. ion) Found m/z: 430, (M+H)+.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:8]([CH:9](Br)Br)=[N:7][CH:6]=[CH:5][N:4]=1.[C:13]([O:22][CH2:23][CH3:24])(=[O:21])/[CH:14]=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Na+].[I-]>CN(C=O)C>[CH2:23]([O:22][C:13]([C:14]1[CH:2]=[C:3]2[C:8](=[CH:9][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]=[CH:6][CH:5]=[N:4]2)=[O:21])[CH3:24]
Reactant: BrC(Br)c1nccnc1C(Br)Br
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nccnc2cc1C(=O)OCC
Temperature: 80 °C
Yield: 36.9 %

Procedure:
To a solution of 38.0 g (90.0 mmol) 2,3-bis-dibromomethyl-pyrazine and 70.0 g (400 mmol) diethyl maleate in 450 ml DMF is added 40.0 g (270.0 mmol) NaI and the mixture is heated at a temperature of 80° C. during 20 hours. After evaporation of the solvent, the residue is dissolved in 1000 ml t-butyl-methyl ether and washed with a 5% sodium thiosulfate solution and water (5 times). Evaporation of the solvent and purification of the residue with flash-chromatography yielded 9.1 g dark oil (37%). 1H-NMR (CDCl3, 400 MHz): 1.45 ppm (t, 6H), 4.45 (q, 4H), 8.5 (s, 2H), 9.0 (s, 2H).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:19][CH2:20][OH:21])[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:19][CH2:20][O:21][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reaction time: 2 h

Procedure:
Combine 1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.15 g, 0.3 mmol) and dichloromethane (5 mL). Cool in an ice bath. Add N,N,-diisopropylethylamine (0.12 mL, 86.5 mg, 0.67 mmol), and methanesulfonyl chloride (0.035 mL, 52 mg, 0.46 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with aqueous 1 M hydrochloric acid solution, water, and then a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.23 (silica gel, ethyl acetate).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(C)=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:1]([CH2:4][N:5]2[C:9]([SH:10])=[N:8][N:7]=[N:6]2)=[O:2])[CH2:28][CH2:27]1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cn1nnnc1S
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cn2nnnc2S)CC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
To a solution of 1-carboxymethyl-1H-tetrazole-5-thiol (3.2 g) in dry acetone (60 ml) was added triethyl amine (4.2 g). After the addition of a solution of pivaloyl chloride (4.8 g) in dry acetone (10 ml) with stirring at -15° C. over a period of 5 minutes, the mixture was stirred for one hour and 15 minutes at the same temperature. A solution of 1-methylpiperazine (4.0 g) in dry acetone (10 ml) was dropwise added over a period of 5 minutes and the resulting mixture was stirred at -15° C. for 40 minutes and under ice-cooling for a further 2.5 hours. After the evaporation of the reaction mixture under reduced pressure, water was added to the residue, 4N aqueous solution of sodium hydroxide was added until the crystals were dissolved. The resulting solution was evaporated under reduced pressure and the residue was crystallized from water to give 1-(4-methyl-1-piperazinyl)carbonylmethyl-1H-tetrazole-5-thiol (2.2 g). mp>250° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N)cc1F
Temperature: 110 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
To a mixture of 4-bromo-3-fluoroaniline (13.3 g, 70.0 mmol), ethyl acrylate (9.48 mL, 87.5 mmol), tris(2-methylphenyl)phosphine (8.52 g, 28.0 mmol), N,N-diisopropylethylamine (50 mL) and N,N-dimethylformamide (50 mL) was added palladium(II) acetate (0.786 g, 3.50 mmol), and the mixture was stirred at 110° C. for 5 hr under an argon atmosphere. The reaction mixture was cooled, and the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was filtered off through celite. The filtrate was separated into the aqueous layer and the organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-60:40) to give the title compound (14.0 g, yield 96%). A part thereof was recrystallized to give yellow prisms.
Reaction SMILES: Cl.[NH:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:22])=[N:5][N:4]=[N:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1)[C:51](O)=[O:52]>O.CN(C=O)C.C(N(CC)CC)C>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([C:51]([N:15]2[CH2:16][CH2:17][C:12]3([CH2:11][C:10](=[O:22])[C:9]4[C:19](=[CH:20][CH:21]=[C:7]([C:6]5[NH:2][N:3]=[N:4][N:5]=5)[CH:8]=4)[O:18]3)[CH2:13][CH2:14]2)=[O:52])[CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1
Reactant: COc1cc(C(=O)O)cc(-c2ccccc2)n1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(Tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (42 mg), 1-hydroxybenzotriazole monohydrate (20 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg), triethylamine (21 μL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 2-methoxy-6-phenyl-isonicotinic acid (25 mg), and stirred at room temperature for 2 hours. Water was added to the reaction liquid, the formed precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1.0H, d, J=2.0 Hz), 8.23 (1.0H, dd, J=8.6, 2.4 Hz), 8.13 (2.0H, d, J=6.8 Hz), 7.57 (1.0H, br s), 7.51-7.44 (3.0H, m), 7.32 (1.0H, d, J=8.6 Hz), 6.78 (1.0H, br s), 4.31-4.27 (1.0H, m), 3.97 (3.0H, s), 3.40-3.20 (3.0H, m), 2.97 (2.0H, s), 2.10-2.05 (1.0H, m), 1.90-1.83 (3.0H, m). MS [M−H]−=495.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27].O>CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCN(CCCCl)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 10.65 g of 4-(4-fluorobenzamido)piperidine (preparation 2) and potassium carbonate (9.93 g) in 160 ml of dry dimethylformamide was cooled to 0° C. and a solution of 1-bromo-3-chloropropane (5.68 ml) in 5.68 ml of dry dimethylformamide added dropwise thereto. After 3 hours at room temperature the reaction mixture was poured into 1600 ml of water and stirred for one hour. The solid which precipitated was recovered by filtration (7.1 g).
Reaction SMILES: [C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][PH:15](=[O:17])[OH:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[Na+:28].C(=O)=O>>[C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][PH:15](=[O:16])[O-:17])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:28]
Reactant: O=[PH](O)Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Product: O=[PH]([O-])Cc1ccc(P(c2ccccc2)c2ccccc2)cc1

Procedure:
15.0 g (44.1 mmol) of (4-diphenylphosphinophenyl)methylphosphinic acid were admixed with 100 ml of a 3.7% strength by weight sodium hydrogen carbonate solution (44.1 mmol of NaHCO3) and stirred at room temperature until CO2 evolution had ceased. The aqueous solution was completely evaporated and dried under reduced presure. This gave 15.6 g (97% of theory) of sodium (4-diphenylphosphinophenyl)methyl-phosphinate. Solubility in water: 590 g/l.