Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:69][C:65]2[CH:66]=[CH:67][CH:68]=[C:63]([C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[C:35]([C:39]5[N:43]=[CH:42][N:41]([C:44]([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)([C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=6)[N:40]=5)[CH:34]=4)[N:30]([CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][O:24]4)[N:31]=3)[CH:64]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-fluorophenyl)acetic acid (0.102 g, 0.66 mmol) in 3.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.140 g, 0.726 mmol). The solution was stirred a t room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.330 mmol), dissolved in 2 mL of dichloromethane was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. (Yield not calculated) ES-MS (m/z) 739 [M+H]+.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C(N(CC)CC)C.[C:25]([Si:29]([CH3:32])([CH3:31])Cl)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O.C(OCC)(=O)C>[Si:29]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reaction time: 6 h
Yield: 88.4 %

Procedure:
5'-O-tert-Butyldimethylsilylthymidine (Compound 2, Table I) was prepared by dissolving thymidine (25 g, 0.10 mole), 4-N,N-dimethylaminopyridine (3.15 g, 0.026 mole) and triethylamine (13.5 g, 18.6 ml, 0.13 mole) in 200 ml of dry N,N-dimethylformamide under a stream of argon. 19.4 g (0.13 mol) tert-butyldimethylchlorosilane was added to the dissolved mixture, with the entire mixture then being stirred for six hours before evaporation of the solvent. The resulting gum was dissolved in 30 ml ethyl acetate and the solution extracted with 10 ml saturated sodium bicarbonate solution, 30 ml water and 30 ml brine. Following drying of the organic layer, the residue was purified by flash chromatography using dichloromethane/ethanol (50/1) as eluent. Evaporation of the product-containing fractions yielded 31.5 g of the desired 5'-O-tert-butyldimethylsilylthymidine as a white foam (86% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Cl-:1].[O:9]=[C:7]1[N:6]2[CH:10]=[CH:11][S:12][C:5]2=[N:4][C:3]([CH2:2][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8]1
Reactant: O=c1cc(CCl)nc2sccn12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Product: [Cl-]

Procedure:
To a stirred suspension of Step 1 intermediate (6.0 g, 29.90 mmol) in acetonitrile was added triphenylphosphine (8.6 g, 32.89 mmol) at room temperature. The resulting reaction mixture was slowly heated to reflux for 30 min. The solvent was concentrated in vacuo and the residue stirred with diisopropyl ethyl ether and filtered. The solid was dried under vacuum to afford 13.5 g of the desired compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 4.96 (d, J=15.0 Hz, 2H), 6.15 (br s, 1H), 7.32 (br s, 1H), 7.60-7.74 (m, 15H), 7.86 (br s, 1H); ESI-MS (m/z) 427.33 (M+H)+.
Reaction SMILES: OC[C:3]([CH2:7]O)([CH2:5][OH:6])[NH2:4].[Cl-].[Cl-].[Ca+2].F[C:13](F)(F)[C:14]([OH:16])=[O:15].FC(F)(F)C(O)=[O:22].C(#N)C>>[NH2:4][C@H:3]([C:5]([OH:6])=[O:22])[CH2:7][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: NC(CO)(CO)CO
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC#N
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
The oligopeptides prepared as described in Example 2 were individually dissolved in PSA digestion buffer (12 mM tris(hydroxymethyl)-aminomethane pH8.0, 25 mM NaCl, 0.5 mM CaCl2) and the solution added to PSA at a molar ration of 100 to 1. The reaction is quenched after various reaction times by the addition of trifluoroacetic acid (TFA) to a final 1% (volume/volume). The quenched reaction was analyzed by HPLC on a reversed-phase C18 column using an aqueous 0.1% TFA/acetonitrile gradient.The results of the assessment are shown in FIG. 2. Other oligopeptides prepared as described in Example 2 were tested in the same assay wherein the reaction was quenched at 4 hours. Those results of the assessment are shown in FIG. 3. The removal of an asparagine residue from the amino terminus of the oligopeptide results in a significant loss of PSA mediatedpeptide hydrolysis, while the presence of a glutamic acid residue at the carboxyl end of the peptide appears not to be essential to recognition by PSA.
Reaction SMILES: N1C2C=CC=CC=2NC=1C(O)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.COC1C=CC(N2CCOCC2)=CC=1N.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:44][C:43]=1[NH:54][C:55]([C:57]1[NH:61][C:60]2[CH:62]=[CH:63][CH:64]=[CH:65][C:59]=2[N:58]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:75])=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.O>[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:44][C:43]=1[NH:54][C:55]([C:57]1[NH:61][C:60]2[CH:62]=[CH:63][CH:64]=[CH:65][C:59]=2[N:58]=1)=[S:75]
Reactant: COc1ccc(N2CCOCC2)cc1NC(=O)c1nc2ccccc2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: COc1ccc(N2CCOCC2)cc1N
Agent: O=C(O)c1nc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)cc1NC(=S)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a suspension of 0.19 g of benzoimidazole-2-carboxylic acid (1.0 mmol) in 4 ml DMF was added 0.21 g of CDI (1.3 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 0.25 g of 2-methoxy-5-morpholin-4-yl-phenylamine (1.2 mmol) was added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with methylene chloride. The combined organic phases were dried on sodium carbonate, evaporated and the residue was stirred in hot ethyl acetate. After filtration and trying 0.27 g 1H-benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (63%) were obtained as a yellow solid; M.p.: 236–237° C. 0.2 g of 1H-Benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.71 mmol) was taken up in toluene (15.0 ml) and treated with 0.28 g of Lawesson reagent (0.71 mmol). The reaction mixture was heated to reflux for 2 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 1:2, then ethyl acetate). 0.22 g of 1H-Benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (86%) was obtained as a yellow solid; M.p.: 240–241° C. 0.19 g of 1H-Benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.52 mmol) were taken up in water (5.0 ml) and treated with 0.116 g KOH (2.0 mmol) and 0.68 g of potassium hexacyano ferrate (2.0 mmol) at reflux for 24 h. After cooling to ambient temperature water (10 ml) was added and the mixture was filtered. The residue on the filter was dissolved in methanol and subjected to column chromatography (silica gel, methylene chloride/methanol 99:1). One obtained 0.089 g of 2-(1H-benzoimidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (39%) as a yellow solid; M.p.: 284–286° C.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].II.[Cl:24]Cl>C(Cl)(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([Cl:24])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)cc1
Reactant: ClCl
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl α-hydroxy-γ-(4-cyclohexylphenyl)butyrate 0.38 mole and 6.1 g. of iodine (0.048 mole) and dissolved in 100 ml. of carbon tetrachloride. To this solution is added a solution of 40.4 g. (0.57 mole) of chlorine dissolved in 365 ml. of carbon tetrachloride over a period of 2 hours. During the addition, the temperature of the reaction mixture is maintained at 0°C. The mixture is stirred for 3 hours and allowed to stand with gradual warming to room temperature over 15 hours. The solvent is removed by distillation under reduced pressure. The residue is fractionally distilled to obtain ethyl α-hydroxy-γ-(3-chloro-4-cyclohexylphenyl)butyrate.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1.NC(N)=[S:13].O1CCCC1>O>[SH:13][C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1
Reactant: COC(=O)c1nsc(Cl)n1
Reactant: NC(N)=S
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nsc(S)n1
Reaction time: 6.5 h
Yield: 92.4 %

Procedure:
A mixture of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (7.80 g), thiourea (3.32 g), tetrahydrofuran (24 ml) and water (8 ml) was gently boiled for 6.5 hours. The reaction mixture was post-treated according to conventional manner to give yellow powder of methyl 5-mercapto-1,2,4-thiadiazole-3-carboxylate (7.1 g), mp. 126° to 127° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:29]=[C:17]2[N:18]=[C:19]([N:23]([CH3:28])[CH2:24][CH2:25][NH:26][CH3:27])[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:29]=[C:17]2[N:18]=[C:19]([N:23]([CH3:28])[CH2:24][CH2:25][N:26]([CH3:27])[CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: CNCCN(C)c1nc(N)n2nc(-c3ccco3)nc2n1
Reactant: Cc1cc(CCl)no1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(CN(C)CCN(C)c2nc(N)n3nc(-c4ccco4)nc3n2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-N5-methyl-N5-(2-methylamino-ethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.14 mmol) and Et3N (0.3 mmol), in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.90 (br s, 2H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1 H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.30 (s, 1H), 3.65 (m, 2H), 3.20-2.75 (m, 4H), 2.5 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H) ppm. MS: m/z: 385 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2ccnc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 10.5 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.24 mmol) in DCM (10 mL) was added TEA (3 drops), followed by acryloyl chloride (32 mg, 0.36 mmol). The mixture was stirred at RT for 1 min and partitioned between DCM (50 mL) and brine (50 mL). Organic layer was separated from aqueous layer, dried over Na2SO4, concentrated and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 12 mg (11%) of 7-(3-acrylamido phenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.80 (d, J=4.4 Hz, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.47 (br s, 1H), 7.42-7.37 (m, 3H), 7.15 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.44 (dd, J=10.1, 16.9 Hz, 1H), 6.26 (dd, J=1.6, 16.9 Hz, 1H), 5.76 (dd, J=1.6, 10.1 Hz, 1H). MS (ESI) m/e [M+1]+ 476.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=[O:17])[S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(CC(C)C)=O>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[NH:13][C:14](=[O:17])[S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:31][CH2:32]2)=[N:19]1
Reactant: O=c1[nH]c(-c2ccc(CCCCCl)cc2)cs1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c(-c2ccc(CCCCN3CCN(c4nsc5ccccc45)CC3)cc2)cs1
Yield: 59.4 %

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.10 g (4.11 mmol) 4-(4-(4-chlorobutyl)phenyl)-thiazol-2-one, 0.90 g (4.11 mmol) N-(3-benzoisothiazolyl)piperazine, 0.87 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 40 ml methylisobutylketone. The reaction mixture was heated at reflux for 44 hours, cooled, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent, and the product fractions collected and evaporated. The residue was taken up in methylene chloride/methanol, treated with ether saturated with HCl, and evaporated. The resulting solid was triturated with acetone to afford 1.10 g (55%) of white solid, m.p. 140-145° C. NMR (DMSO-d6): 1.6-1.8 (m, 4H), 2.62 (t, 2H), 3.1-3.3 (m, 4H), 3.4-3.6 (m, 4H), 4.0-4.1 (m, 2H), 6.75 (d, 1H), 7.2-8.1 (m, 8H).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>CO>[N:27]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[CH:14]=[C:9]2[CH:8]=[CH:7][NH:6][C:10]2=[N:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3ccccc3Oc3ncccn3)cnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1cnc(Oc2ccccc2-c2cnc3[nH]ccc3c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A mixture of 40 prepared above (120 mg, approx. 0.24 mmol), MeOH (1.1 mL) and 10% aq. HCl (2.4 mL) were stirred at room temperature for 1 h then poured onto saturated aq. NaHCO3/ethyl acetate. The aqueous phase was extracted with more ethyl acetate and the combined organic extracts dried (MgSO4) and concentrated to give pure product 41 (40.8 mg, 44% over 3 steps from 26); 1H NMR (400 MHz, CDCl3) δ 6.40 (dd, J=3.4, 1.6 Hz, 1H), 6.76 (t, J=4.8 Hz, 1H), 7.21 (m, 2H), 7.32 (dt, J=7.8 Hz, 1.8 Hz, 1H), 7.39 (dt, J=7.8, 1.8 Hz, 1H), 7.46 (dd, J=7.5, 1.8 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.30 (d, J=4.8 Hz, 2H), 8.37 (d, J=2.0 Hz, 1H), 10.26 (bs, NH).
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CC(N(C)C)=O>[CH3:6][C:3]([CH3:7])([CH2:2][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:4][OH:5]
Reactant: C1CCNCC1
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)CN1CCCCC1
Yield: 18.5 %

Procedure:
A solution of 3.00 g (17.96 mmol) of 3-bromo-2,2-dimethyl-propan-1-ol, 17.78 ml (179.59 mmol) of piperidine, 2.48 g (17.96 mmol) of K2CO3 and 2.69 g (17.96 mmol) of potassium iodide in 20 ml of DMA were stirred at 70° C. for 20 h. After filtration and evaporation of the solvents, the crude product was dissolved in diluted aqueous HCl solution and washed with EtOAc (3×). The aqueous phase was basified with KHCO3 and some drops of 1N NaOH and extracted with EtOAc (3×). The organic phase was dried (Na2SO4) and evaporated to give 0.57 g (18%) of the title compound as yellow liquid. MS: 172.0 (MH+).
Reaction SMILES: C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[Cl:78][C:79]1[CH:84]=[C:83]([Cl:85])[CH:82]=[CH:81][C:80]=1[C:86](=O)[CH2:87][C:88]#[N:89].C1C(=O)N(Br)C(=O)C1.[NH2:99][C:100]([NH2:102])=[S:101]>O.CC(C)=O>[NH2:102][C:100]1[S:101][C:87]([C:88]#[N:89])=[C:86]([C:80]2[CH:81]=[CH:82][C:83]([Cl:85])=[CH:84][C:79]=2[Cl:78])[N:99]=1
Reactant: N#CCC(=O)c1ccc(Cl)cc1Cl
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1Br
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1sc(N)nc1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 41.9 %

Procedure:
beta-Cyclodextrin (4.29 g, 3.78 mmol) was dissolved in water (75 mL) at 50° C. and a solution of 3-(2,4-dichlorophenyl)-3-oxopropanenitrile (810 mg, 3.8 mmol) in Acetone (3.80 mL) was added dropwise, followed by NBS (0.808 g, 4.54 mmol) and thiourea (0.346 g, 4.54 mmol). Reaction mixture was stirred at 50° C. 1 hr. LCMS indicated complete conversion. Reaction mixture was cooled to rt, extracted with ethyl acetate (3×50 mL), dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO with 5-30% ethyl acetate in hexanes to give 0.43 g of the title compound (42%). LCMS: (FA) ES+, 270, 272. 1H NMR (400 MHz, d1-chloroform) δ 7.49 (d, J=1.84 Hz, 1H), 7.41 (d, J=8.30 Hz, 1H), 7.31 (dd, J=8.16, 1.74 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].C[Al](C)C.ClC1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:22](=[O:40])[NH:23][CH:24]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)[C:25]([F:28])([F:27])[F:26])[N:17]2[CH2:20][CH3:21])=[CH:13][C:12]=1[C:41]([O:43]CC)=O.O.Cl[CH2:48][Cl:49]>>[Cl:49][C:48]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:22]([NH:23][CH:24]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:30]=3)[C:25]([F:28])([F:26])[F:27])=[O:40])[N:17]2[CH2:20][CH3:21])=[CH:13][C:12]=1[C:41]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[O:43]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3ccc(F)c(C(F)(F)F)c3)C(F)(F)F)n(CC)c2cc1Cl
Reactant: NCC(F)F
Reactant: ClCCl
Agent: C[Al](C)C
Solvent: O
Product: CCn1c(C(=O)NC(c2ccc(F)c(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NCC(F)F)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2,2-Difluoroethanamine (0.12 g, 1.42 mmol) was dissolved under argon in dichloromethane (2 ml). At room temperature, a solution of trimethylaluminium in dichloromethane (0.71 ml, 1.42 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min and then a solution of ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (0.078 g, 0.14 mmol) in dichloromethane (2 ml) was added dropwise. The reaction mixture was heated under reflux for 16 h and, after cooling, water was added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.065 g (81% of theory) of 6-chloro-N5-(2,2-difluoroethyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[Br:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:28]Br)=[CH:23]2>>[Br:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:28][O:16][C:4]1[CH:5]=[C:6]([C:8]3([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:7]=[C:2]([F:1])[CH:3]=1)=[CH:23]2
Reactant: BrCc1ccc2c(Br)cccc2c1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Product: COC1(c2cc(F)cc(OCc3ccc4c(Br)cccc4c3)c2)CCOCC1
Yield: 52 %

Procedure:
Using the procedure described in Example 5, 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran was reacted with 5-bromo-2-bromomethylnaphthalene to give 4-[3-(5-bromonaphth-2-ylmethoxy)-5-fluorophenyl]-4-methoxytetrahydropyran in 52% yield, as an oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[C:5]([O:14]CC)(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]([OH:14])=[O:13])[CH2:2][CH3:3]
Reactant: CCCBr
Reactant: CCOC(=O)c1ccccc1O
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1ccccc1C(=O)O

Procedure:
The reaction of propyl bromide and ethyl salicylate in the presence of potassium carbonate was performed as described for Compound 24 to give 2-Propoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.56 (s, COOH); 7.61 (m, 1 arom. H); 7.45 (m, 1 arom. H); 7.07 (m, 1 arom. H); 6.96 (m, 1 arom. H); 3.96 (t, CH3CH2CH2O); 1.71 (m, CH3CH2CH2O); 0.96 (t, CH3CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.49 (—C═O); 157.41; 132.82; 130.51; 121.73; 119.91; 113.35; 69.63; 22.04; 10.39.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH2:17][CH2:18]Br>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:17][CH3:18]
Reactant: N#Cc1ccccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1C#N

Procedure:
75 g (630 mmol) of 2-hydroxybenzonitrile, 174 g (1.26 mol) of potassium carbonate and 232.3 g (1.89 mol) of n-propyl bromide in 1 1 of acetone are refluxed overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. B.p.: 89° C. (0.7 mbar)