Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.C([CH:31]([C:35]1[S:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[N:37][CH:36]=1)[C:32]([O-:34])=[O:33])C=C>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:25])([F:27])[F:26])[CH:5]=[CH:4][C:3]=1[CH2:2][O:46][C:43]1[CH:42]=[CH:41][C:40]([C:38]2[S:39][C:35]([CH2:31][C:32]([OH:34])=[O:33])=[CH:36][N:37]=2)=[CH:45][CH:44]=1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: C=CCC(C(=O)[O-])c1cnc(-c2ccc(O)cc2)s1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ncc(CC(=O)O)s3)cc2)ccc(C(F)(F)F)c1O
Yield: 9 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (11-7), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (314 mg, 0.69 mmol) obtained in Example (28-5) and allyl[2-(4-hydroxyphenyl)-1,3-thiazol-5-yl]acetate (190 mg, 0.69 mmol) obtained in Example (30-2), the title compound was obtained as a colorless powder (33 mg, three-step total yield: 9%).
Reaction SMILES: C(=O)(O)O.[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[O:15]C(=O)OC(C)(C)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)[CH:24]=1.[OH-].[K+]>CO.O>[F:5][C:6]1[C:11]([CH:12]([OH:13])[C:37]2[C:31]3[C:32](=[N:33][CH:34]=[C:29]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH:30]=3)[NH:35][CH:36]=2)=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[OH:15]
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C=O)c1F
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To carbonic acid tort-butyl ester 2,4-difluoro-3-formyl-phenyl ester (39, 0.405 g, 15.7 mmol) in methanol (36 mL), under an atmosphere of nitrogen, was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 288.0 mg, 14.8 mmol, prepared as in Example 17, Scheme 32) and potassium hydroxide (145.0 mg, 25.9 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 4% methanol in methylene chloride to give a colorless oil (P-0009, 0.23 g, 44.1%). MS(ESI) [M+H+]+=354.1.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[C:25]([F:27])[C:24]([OH:28])=[C:23]([F:29])[CH:22]=1)=[O:17]>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:24]3[C:23]([F:29])=[CH:22][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:26][C:25]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 88 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 23 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (0.020 g, 0.08 mmol) obtained in Step C of Preparation Example 60 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.030 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](=[S:20])[NH:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:22]([CH3:25])(=[O:24])=[O:23])[CH3:2].IC.[CH:28](N(C(C)C)CC)(C)[CH3:29]>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18]([S:20][CH2:28][CH3:29])=[N:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:22]([CH3:25])(=[O:23])=[O:24])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(=S)NC3=O)cc12
Solvent: CC#N
Solvent: CI
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(SCC)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41b was used, starting from 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (example 74d), iodomethane, and DIEA (diisopropylethylamine) in acetonitrile to give 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-ethylsulfanyl-thiazol-4-one. LC-MS m/e 409 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.O=S(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 90 °C
Yield: 70 %

Procedure:
To a mixture of 6-iodoquinazolin-4(3H)-one (1.70 g, 6.25 mmol) in SOCl2 (10 mL) was dropped a few drops of DMF, and then it was heated at 90° C. for 5 hours. After excess SOCl2 was removed under reduced pressure, to it was added CH2Cl2 and water, and neutralized with saturated NaHCO3 solution. The aqueous was extracted with CH2Cl2 three times. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford 4-chloro-6-iodoquinazoline as solid (1.266 g, 70%). 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.67 (d, 1H), 8.22 (dd, 1H), 7.81 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:21][Ti:22](Cl)([Cl:33])[C:23]1([CH3:32])[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([CH3:30])=[C:24]1[CH3:31]>C(OCC)C>[Cl:21][Ti:22]([Cl:33])([C:23]1([CH3:32])[C:24]([CH3:31])=[C:25]([CH3:30])[C:26]([CH3:29])=[C:27]1[CH3:28])[O:15][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(C(C)(C)C)cccc2C(C)(C)C)C(C)=C1C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
After 600 mg of 2,6-di-tert-butylphenol (2.91 mmol) (Aldrich, 99%) were dissolved in 30 mL of diethylether, 1.28 mL of butyl lithium (2.5 M hexane solution) were slowly dropped thereonto at −31° C. After 1 hour, agitation was conducted at normal temperature for 6 hours. The resulting mixture was dissolved in diethylether, and a solution in which (trichloro)(pentamethylcyclopentadienyl)titanium(IV) (752 mg, 2.60 mmol) was dissolved in 10 mL of diethylether was slowly dropped thereonto at −30° C. After 1 hour, agitation was conducted at normal temperature for 6 hours. The solvent was removed from the resulting product, and the solvent-free product was dissolved in 10 mL of toluene and then recrystallized to produce 829 mg of red solid component.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O.Cl.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[NH:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]2[NH:28][C:7](=[O:9])[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:11]([OH:13])[N:27]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: COc1ccc(C(=N)N)cc1
Agent: Cl
Product: COc1ccc(-c2nc(O)c(Oc3ccccc3OC)c(=O)[nH]2)cc1

Procedure:
In analogy to Example 1, paragraph d), 7.63 g of dimethyl (o-methoxyphenoxy)malonate and 5.6 g of p-methoxy-benzamidine hydrochloride were condensed to give 2-(p-methoxyphenyl)-5-(o-methoxyphenoxy)-6-hydroxy-4(3H)-pyrimidinone. Reaction of this compound in analogy to Example 1, paragraph e), yielded 4,6-dichloro-2-(p-methoxyphenyl)-5-(o-methoxyphenoxy)-pyrimidine, m.p. 113°-114° C., from which in analogy to Example 1, paragraph f), there was obtained p-tert-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(p-methoxyphenyl)-4-pyrimidinyl]benzenesulfonamide, m.p. 221°-222° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28](Cl)=[O:29])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1.Cl>O1CCCC1.O>[OH:3][NH:2][C:28](=[O:29])[CH:27]=[CH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17](=[O:19])(=[O:18])[NH:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:21]=1
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.31 g, 4.40 mmol) in tetrahydrofuran (5 ml) a saturated NaHCO3 solution (6-8 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (16b) (0.29 g, 0.86 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into water, the obtained solution was acidified with 2N HCl to pH˜5 of the reaction medium and extracted with ethyl acetate. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was washed with hot ethyl acetate and methanol affording the title compound (0.12 g, 37%). M.p. 191° C. 1H NMR (DMSO-d6, HMDSO) δ: 4.05 (2H, d, J=6.4 Hz); 6.56 (1H, d, J=16.0 Hz); 7.16-8.05 (7H, m); 8.16-8.49 (3H, m); 9.12 (1H, br s); 10.80 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 8% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 10:90; sample concentration 0.4 mg/ml; flow rate 1.3 ml/min; detector UV 270 nm). Anal. Calcd for C15H15N3O4S containing 0.5% of inorganic impurities, %: C 53.77, H 4.51, N 12.54. Found, %: C 53.72, H 4.33, N 12.41.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=O)[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[NH2:52][OH:53]>>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])/[C:7](=[N:52]\[OH:53])/[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: NO
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)/C(=N\O)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
reacting the C-9 ketone of erythromycin A with hydroxylamine to form erythromycin oxime;
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([NH2:13])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14](Br)[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CC(C)=O>[CH2:14]([O:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([NH2:13])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: NC(=O)c1cc2c(O)cccc2o1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cccc2oc(C(N)=O)cc12
Temperature: 0 °C
Yield: 99.4 %

Procedure:
A mixture of 1 g (5.64 mmol) of 4-hydroxybenzofuran-2-carboxamide, 0.5 ml (6.77 mmol) of ethyl bromide, 1.56 g (11.3 mmol) of potassium carbonate, 6 ml of anhydrous DMF and 50 ml of anhydrous acetone was heated at reflux over 24 hours. Subsequently, the mixture was poured on to 70 ml of ice-water, extracted twice with 100 ml of ethyl acetate each time and the combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. There were obtained 1.15 g (99%) of 4-ethoxybenzofuran-2-carboxamide as a yellow solid with m.p. 113°.
Reaction SMILES: ClC(Cl)C(Cl)=[O:4].Cl[CH:8](Cl)[C:9]([N:11]([CH2:15][CH2:16][C:17]1[N:18]=[C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[CH3:33])(=[O:25])=[O:24])[S:20][CH:21]=1)[CH2:12][CH2:13][OH:14])=[O:10].[OH-].[K+].Cl>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.O>[Cl:32][C:28]1[C:27]([CH3:33])=[C:26]([S:23]([NH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][CH2:15][N:11]3[CH2:12][CH2:13][O:14][CH:8]([OH:4])[C:9]3=[O:10])[N:18]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN(CCO)C(=O)C(Cl)Cl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN2CCOC(O)C2=O)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a slurry of EXAMPLE 208A (0.759 g, 2.02 mmol) in ethyl acetate (6 mL) and saturated sodium carbonate (6 mL) at 0° C., 2,2-dichloroacetic acid chloride was added neat in portions (15×40 μl 3 eq.). The mixture was stirred for 1.5 h at room temperature. The reaction mixture was then extracted with ethyl acetate (3×40 mL), washed with brine (40 mL), and dried over magnesium sulfate. The solvent was evaporated and 1.10 g of crude N-acetylated product was isolated as yellow oil (70% pure by HPLC). The crude 2,2-Dichloro-N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)ethyl]-N-(2-hydroxyethyl)acetamide (1.00 g, 2.05 mmol) was dissolved in THF (27 mL) and water (27 mL). The solution was cooled to 0° C. and the pH was adjusted to 14-15 with aqueous KOH (50%). After 20 h, the reaction mixture was neutralized with aqueous HCl (1 M, 12 mL). The reaction mixture was extracted with ethyl acetate (3×25 mL), and the combined organic phases was dried over magnesium sulfate. Removal of solvent and purification by silica gel chromatography (gradient of 2-4% methanol in DCM) gave the title compound as a white solid (20 mg): HRMS calcd (found) for C16H18ClN3O5S2 m/z 431.0376 (431.0380).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1>C(O)C.[Rh]>[NH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1
Reactant: CCOC(=O)Cc1ccc(CCCN)cc1
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCC(CCCN)CC1
Yield: 90 %

Procedure:
by hydrogenation of ethyl 4-(3-aminopropyl)-phenylacetate hydrochloride in the presence of rhodium in ethanol. Yield 90% of theory; m.p. 99°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH:26]1([Mg]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCOCC.Cl.C([O-])(O)=O.[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH:26]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:25])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=3)[CH2:14][CH2:13]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=C(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OC(CCCN1CCN(c2ncc(F)cn2)CC1)(c1ccc(F)cc1)C1CCCCC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A cold (15° C.) solution of 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanone (2.1 g, 6.1 mmol) in dry tetrahydrofuran (25 mL) kept under argon atmosphere was treated dropwise (15 min) with a solution of cyclohexylmagnesium chloride in ether (2.0M, 3.18 mL, 6.36 mmol). The cooling bath was removed and reaction mixture after being stirred at 23° C. for 2 h was treated dropwise (15 min) with HCl (2N, 3.5 mL), stirred for 15 min and diluted with CHCl3 (50 mL). The organic phase was basified with NaHCO3 and separated. Aqueous phase was extracted with CHCl3 (15 mL). The organic extracts were dried (MgSO4) and concentrated in vacuo to a sticky solid which was purified on silica gel column using a mixture of 40-100% AcOEt in CHCl3 as eluting solvent. The first group of fractions was concentrated in vacuo to give the carbinol as a solid, 1.1 g, 42%. The second group of fractions gave, after evaporation of solvent, the initial ketone 1.0 g, 48%. The carbinol was recrystallized from EtOH to give an analytical sample, mp 53°-9° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH2+:19]1.C1(S([O-])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2
Reactant: O=C1CCCc2cc(OCCCCl)ccc21
Reactant: C[C@@H]1CCC[NH2+]1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [I-]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCCC2=O

Procedure:
In a 1 L round bottom flask, 6-(3-chloro-propoxy)-3,4-dihydro-2H-naphthalen-1-one (10.0 g, 41.9 mmol), benzenesulfonate (R)-2-methyl-pyrrolidinium (13.15 g, 84.0 mmol), potassium carbonate (23.15 g, 168 mmol), and potassium iodide (100 mg, 0.6 mmol) in acetonitrile (600 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, then washed with water three times. The organics were extracted three times with 3% citric acid solution. The combined aqueous layers were basified with sat. NaHCO3 sol. and extracted with methylene chloride, then dried over MgSO4. Ethereal HCl was added and the solvents reduced under vacuum. Crystallization from MeOH/Et2O produced 8.75 g (65%). Mp 183-185° C. MS m/z=288 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](C3C=CC=C(Br)C=3)[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2=CC3NC4C(C=3C=C2C2C1=CC=CC=2)=CC=CC=4.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]1([C:10]2[N:11]=[CH:12][N:13]=[C:8]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:9]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cccc(-c2nc(-c3ccccc3)nc(-c3cccc(Br)c3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: c1ccc(-c2ncnc(-c3ccccc3)n2)cc1

Procedure:
10.9 g (23.5 mmol) of 2,4-bis(3-bromophenyl)-6-phenyl-1,3,5-triazine, 13.3 g (47 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene and 29.2 g of Rb2CO3 are suspended in 250 ml of p-xylene. 0.95 g (4.2 mmol) of Pd(OAc)2 and 12.6 ml of a 1 M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 24 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and evaporated to dryness. The residue is extracted with hot toluene and recrystallised three times from toluene and finally sublimed in a high vacuum, giving 13.1 g (15 mmol), corresponding to 53% of theory. The purity is 99.9%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C.O>[CH2:29]([O:19][C:18]([C:5]1[C:6]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][C:13]3([CH2:15][CH2:14]3)[CH2:16][CH2:17]2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:20])[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: O=C(O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 2-chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid (490 mg) in DMF (2.9 mL) are added K2CO3 (4.4 mmol) and allyl bromide (7.4 mmol) at room temperature. After stirring at 50° C. for 0.5 h, the reaction mixture is cooling and diluted with H2O. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give a crude title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C([O-])(=O)C>CN(C)C=O>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc(I)cc1
Reactant: Oc1ccccc1S
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCc1ccc(Sc2ccccc2O)cc1

Procedure:
A solution of 4-(4-iodophenyl)butyric acid (0.86M) and dimethylformamide was treated with 2 eq of potassium carbonate, 1.5 eq of 2-hydroxythiophenol and a catalytic amount of cuperic acetate (0.01 eq). The reaction mixture was refluxed for 18 hr, cooled to 25 C, acidified with aqueous acid and extracted with ethyl acetate. The organic phase was concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane as eluant to give 4-(4-(2-hydroxyphenyl)thiophenyl)butyric acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1)=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCN(c2ccccc2)CC1
Reaction time: 1 h
Yield: 134.2 %

Procedure:
19.7 g of N-(tert-butoxycarbonyl)tyrosine, 12.5 g of N-phenylpiperazine and 16.1 g of N-hydroxybenzotriazole were dissolved in 100 ml of tetrahydrofuran, and to the solution was added dropwise a solution of 18.7 g of DCC in 50 ml of tetrahydrofuran for 20 minutes with ice cooling, and the mixture was stirred for one hour. The reaction mixture was filtered to remove insoluble matter, which was then washed with 300 ml of ethyl acetate, and the filtrates were combined and concentrated under a reduced pressure. The resulting residue was dissolved in 500 ml of ethyl acetate, and the solution was washed three times with saturated sodium bicarbonate aqueous solution and once with saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with ethyl acetate/hexane (1:2 to 1:1) to collect desired fractions, which were then combined and concentrated under a reduced pressure. Resulting residue was dissolved in 100 ml of ethyl acetate, and the solution was allowed to stand overnight&. in a refrigerator and then filtered to remove insoluble matter. The filtrate was concentrated under a reduced pressure, subjected to azeatropic distillation with benzene and dried under a reduced pressure to obtain 40.0 g of the title compound in a colorless amorphous form.