Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(CCC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)C=CC=1O.Cl.ClCCN1CCCCC1.[F:41][C:42]1[CH:56]=[C:55]([CH2:57][CH2:58][C:59]2[CH:64]=[C:63]([O:65]C)[CH:62]=[CH:61][C:60]=2[CH:67]2[CH2:76][CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[C:72]([O:77]C)[CH:73]=3)[CH2:68]2)[CH:54]=[CH:53][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[F:41][C:42]1[CH:56]=[C:55]([CH2:57][CH2:58][C:59]2[CH:64]=[C:63]([OH:65])[CH:62]=[CH:61][C:60]=2[CH:67]2[CH2:76][CH2:75][C:74]3[CH:73]=[C:72]([OH:77])[CH:71]=[CH:70][C:69]=3[CH2:68]2)[CH:54]=[CH:53][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)c(F)c1)C2
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1CCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Yield: 74.3 %

Procedure:
Synthesized from 2-fluoro-4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{2-fluoro-4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenoxy}ethyl}piperidine (175 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (123 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]=[C:16]([NH2:22])[C:15]=2[N:23]=1)[CH3:9]>>[NH2:22][C:16]1[C:15]2[N:23]=[C:12]([CH2:11][O:10][CH2:8][CH3:9])[N:13]([CH2:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH2:30][CH2:31]3)[C:14]=2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(S(=O)(=O)N(C)C)CC1

Procedure:
Using the method of Examples 49-56, dimethylsulfamoyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 439.2510.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][C:4]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][C:34]=1[C:41]([F:44])([F:43])[F:42]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[C:6]2=[N:5][C:4]=1[N:16]([CH2:37][C:36]1[CH:39]=[CH:40][C:33]([F:32])=[C:34]([C:41]([F:44])([F:42])[F:43])[CH:35]=1)[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH3:2]
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: CCc1c(NS(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of compound 13-E (0.060 g, 0.1 mmol) in DMF (3 mL) was added Na2CO3 (0.032 g, 0.3 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.028 g, 0.11 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 55 as a white solid (0.047 g, 87%); MS m/z (M+H+) 546.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].O[C:8]1[C:9](OCC2C=CC=CC=2)=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:23]([C:24]=2[CH:25]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]1[O:26][CH2:27]C1C=CC=CC=1.[C:42]([CH2:46]I)(F)(F)F>CN(C=O)C>[CH2:1]([O:4][CH:18]([O:26][CH2:27][C:42]1[CH:46]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@:19]12[CH2:21][CH2:22][C@H:23]3[C@@H:14]([CH2:13][CH2:12][C:11]4[CH:10]=[CH:9][CH:8]=[CH:25][C:24]=43)[C@@H:15]1[CH2:16][CH2:17][CH2:20]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:24][CH:25]=1
Reactant: FC(F)(F)CI
Reactant: C[C@]12CC[C@@H]3c4cc(O)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COC(OCc2ccccc2)[C@@]23CCC[C@H]2[C@@H]2CCc4ccccc4[C@H]2CC3)cc1
Temperature: 110 °C
Yield: 233.9 %

Procedure:
Powdered K2CO3 (1.5 g, 11 mmol) was added to a solution of estradiol (6) (4.0 g, 8.5 mmol) in anhydrous DMF (50 mL) followed by dropwise addition of CF3CH2I (5.0 mL, 51 mmol) at room temperature. The resulting reaction mixture was heated at 110° C. for 3 h. Additional K2CO3 (2.5 g) and CF3CH2I (6 mL) were added, and the mixture was heated again at 130° C. for 2 h. The mixture was cooled in an ice bath and poured onto ice cold 3N HCl (125 mL). The aqueous layer was extracted with ether (2×200 mL). The combined ether layer was washed with 3 N HCl (100 mL), water (100 mL), brine (100 mL), and dried over anhydrous MgSO4. The ether layer was evaporated under reduced pressure and the resulting crude product on purification on a silica gel column gave estradiol (7) (4.5 g, 95%) as a colorless oil: IR (neat) 2910, 2850, 1600, 1500, 730, 690 cm-1 ; 1H NMR (CDCl3) δ 0.9 (s, 3 H), 1.1-2.4 (m, 13 H), 2.65-2.85 (m, 2 H), 3.50 (t, J=8.5 Hz, 1H), 4.40 (q, J=8.5 Hz, 2 H), 4.56 (s, 2 H), 5.05 (s, 2 H), 6.70 (s, 1 H), 6.98 (s, 1 H), 7.2-7.55 (m, 10 H). Anal. (C34H37F3O3) C, H.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:14]([C:13]4[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:12]=4[F:11])[CH2:31][NH:30][C:35]3=[O:36])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(C(F)(F)F)cc2F)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.457 g, 3.44 mmol), 2-fluoro-4-(trifluoromethyl)benzaldehyde (0.600 g, 3.13 mmol), TMSCN (0.39 mL, 3.13 mmol), PdC (10%, 0.02 g), TEA (0.455 mL, 3.26 mmol), di-(imidazol-1-yl)methanone (0.529, 3.26 mmol) as described in method 2.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)(=[O:3])[CH3:2]>C(O)C>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(F)c2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2cccc(F)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-2-(3-fluorobenzoyl)-1-(ethoxycarbonyl)indole (step 1). m.p.: 201-202° C. (ethanol)
Reaction SMILES: ClC(Cl)(Cl)COC([CH:7]1[CH:12]2[CH2:13][CH2:14][N:8]1[CH2:9][C:10](=[N:15][N:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11]2)=O>C(O)(=O)C.[Zn]>[C:23]1([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[C:10]2[CH2:9][N:8]3[CH2:14][CH2:13][CH:12]([CH2:7]3)[CH2:11]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C1C2CCN1CC(=NN(c1ccccc1)c1ccccc1)C2
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc(N(N=C2CC3CCN(C2)C3)c2ccccc2)cc1
Reaction time: 0.75 h

Procedure:
Zinc dust (90.0 g) is added in small portions to a well-stirred mixture of 5-(2,2-diphenylhydrazono)-1,3-ethanopiperidine-2-carboxylic acid-2,2,2-trichloroethylester in 300 ml of glacial acetic acid, maintaining the reaction temperature between 40° C.-60° C. with external cooling when necessary. Upon completion of the addition, stirring is continued at ambient temperature for 45 minutes. The insoluble material is filtered and the resulting clear yellow filtrate contains the desired product and can be used in the succeeding Fisher-Indole synthesis procedures.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:28])[CH3:2].[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:37]#[C:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:17]=[C:18]([O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:19]=2)=[CH:9][C:8]=1[CH3:28])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC(CC)CC)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCC(CC)CC)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.42 mmol), (phenyl acetylene (170 mg; 1.66 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 170 mg (82%). HPLC-MS: m/z: 502.9 (M)+; Rt: 3.32 min.
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[O:13][CH:12]([CH3:19])[CH2:11]2>O1CCOCC1>[CH3:19][CH:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][CH:3]=[O:2])[CH:9]=2)[C:14](=[O:18])[O:13]1
Reactant: CC1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: CC1Cc2cc(CC=O)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1:1 solution of dioxane:3N HCl was added to a flask containing of 99 mg (0.49 mmol) of 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one; the reaction was then stirred at room temp overnight. The crude reaction mixture was then partitioned between water and DCM. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[O:10])=[C:4]([Cl:22])[CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:25])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[O:10])=[C:4]([Cl:22])[CH:3]=1
Reactant: CI
Reactant: Cn1c(=O)oc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccc2oc(=O)n(C)c2c1)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
5-[2-(4-Bromo-2-chloro-phenyl)-acetyl]-3-methyl-3H-benzooxazol-2-one (304 mg) was dissolved in DMF (8 mL). The mixture was cooled to 0° C. To this solution was added sodium hydride (60% in mineral oil, 37 mg). The mixture was stirred for 10 minutes at 0° C. and then for 1 hour at r.t. The mixture was cooled to 0° C. and methyl iodide (119 mg) was added dropwise over a period of 10 minutes. Stirring was continued over night at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (238 mg, 76%). MS (neg. ion, m/e)=394.2 [(M−H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Br[CH:11]([CH3:14])[CH:12]=O>C(O)C>[CH3:14][C:11]1[N:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]2=[N:1][CH:12]=1
Reactant: CC(Br)C=O
Reactant: N#Cc1ccc(N)nc1
Solvent: CCO
Product: Cc1cnc2ccc(C#N)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of 6-aminonicotinonitrile (1.2 g, 10.1 mmol) in ethanol (80 mL) was added 2-bromopropanal (6-1) (6.9 g, 50.5 mmol). The reaction mixture was stirred at 80° C. overnight. The solution was concentrated, diluted with water (20 mL) and adjusted to PH>7 with saturated aqueous NaHCO3 solution. The precipitate was collected to afford the title compound (430 mg). MS (m/z): 158 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([C:28]1[NH:32][C:31]([C:33]([OH:35])=O)=[C:30]([Cl:36])[CH:29]=1)=[O:27].[NH2:37][CH2:38][C:39]1[C:40]([F:56])=[C:41]([O:46][C:47]2[CH:48]=[C:49]([CH:52]=[C:53]([Cl:55])[CH:54]=2)[C:50]#[N:51])[C:42]([Cl:45])=[CH:43][CH:44]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:36][C:30]1[CH:29]=[C:28]([C:26]([NH2:25])=[O:27])[NH:32][C:31]=1[C:33]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][C:47]2[CH:48]=[C:49]([C:50]#[N:51])[CH:52]=[C:53]([Cl:55])[CH:54]=2)[C:40]=1[F:56])=[O:35]
Reactant: NC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(N)=O)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 5-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to afford the title compound (0.023 g, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (br. s., 1H), 8.48-8.74 (m, 1H), 7.72-7.98 (m, 2H), 7.27-7.62 (m, 5H), 6.83 (d, 1H), 4.48 (d, 2H). LCMS: m/z 481.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[O:12]1[CH2:17][CH:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C1(C)C=CC=CC=1>[O:12]1[CH2:13][CH:14]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1ccc(C2=CCOCC2)cc1
Yield: 63.5 %

Procedure:
2.2 g (15.1 mmol) of (4-cyanophenyl)boronic acid, 2.5 g (10.8 mmol) of 3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate, 373 mg (0.32 mmol) of tetrakis(triphenylphosphine)palladium(0) and 1.59 g (15.1 mmol) of sodium carbonate were heated under reflux in a mixed solvent comprising 4 mL of H2O, 57 mL of toluene, and 17 mL of methanol for 3 hours. After the completion of the reaction, the organic solvent was distilled off under reduced pressure, H2O was added to the residue, and ethyl acetate extraction was performed. Subsequently, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 1.27 g of 4-(3,6-dihydro-2H-pyran-4-yl)benzonitrile (yield: 64%).
Reaction SMILES: N(OCCCC)=O.[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39](N)=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.II.[I:49]CI>C1COCC1.[Cu]I>[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39]([I:49])=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: ICI
Agent: [Cu]I
Agent: CCCCON=O
Agent: II
Solvent: C1CCOC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
n-Butyl nitrite (4.65 ml, 39.7 mmol) was added to a suspension of (2R,3R,4S,5S)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 46) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7 mmol), copper(I) iodide (6.16 g, 32.3 mmol) and diiodomethane (12.55 ml, 155.8 mmol) in THF (100 ml) and the mixture was heated under reflux for 2.5 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between 5% w/w aqueous sodium metabisulfite solution (100 ml) and dichloromethane (100 ml). The organic layer was separated, filtered through Arbocel (Trade Mark), dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (99:1 by volume) to afford the title compound as a yellow foam (7.55 g).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)C.[OH-].[Li+]>CO.O>[CH2:24]([S:23][CH2:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[O:14][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CSCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Cl)cc1CSCc1ccccc1

Procedure:
[3-(2-Benzylsulfanylmethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester was hydrolyzed with lithium hydroxide in MeOH and H2O to give the title compound.
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:19]C(=O)C)([CH3:18])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16]Br)=[CH:12][CH:13]=1)(=O)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:33])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].N[C@](C)(CCC1OC(C#CCOC2C=CC(Cl)=CC=2)=CC=1)CO>>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH2:19][C@:6]([CH3:18])([CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][O:33][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: COc1ccc(O)cc1OC
Reactant: CC(=O)N[C@](C)(CCc1ccc(C#CCBr)o1)COC(C)=O
Agent: C[C@](N)(CO)CCc1ccc(C#CCOc2ccc(Cl)cc2)o1
Agent: O=C(O)C(=O)O
Product: COc1ccc(OCC#Cc2ccc(CC[C@@](C)(N)CO)o2)cc1OC
Yield: 68 %

Procedure:
The title compound was synthesized in a yield of 68% using (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(3-bromoprop-1-ynyl)furan-2-yl]butane obtained in Example (22b) and 3,4-dimethoxyphenol as the starting materials by conducting successively the reactions similar to those mentioned in Examples (22c) and (22d).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[OH-].[Na+].[CH3:21]I.O>CS(C)=O>[CH3:21][N:7]1[C:6]2[CH:17]=[C:2]([CH3:1])[C:3]([CH3:18])=[CH:4][C:5]=2[NH:11][C:10]2[N:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]1=[O:16]
Reactant: CI
Reactant: Cc1cc2c(cc1C)Nc1ncccc1C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(cc1C)N(C)C(=O)c1cccnc1N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4.55 g (0.019mol) of 6,11-dihydro-8,9-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one in 40 ml of dimethylsulfoxide was added 3.0 ml of a 30% NaOH solution (0.022 mol). After two hours at room temperature 5.0 ml (0.08 mol) of methyl iodide was added and the mixture stirred at room temperature overnight. It was then poured into water, the resulting precipitate collected, washed, dried and crystallized from ethanol to yield 3.3 g (69% of theory) of a crystallized solid melting at 206°-209° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1.[Li+].[OH-]>C(Cl)Cl>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Reactant: CC(=O)OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2sc(S(=O)(=O)Nc3cccc(C(=O)O)c3)c(C)c2c1
Reaction time: 4 h
Yield: 56 %

Procedure:
A solution of methyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (7 mg, 0.019 mmol) in CH2Cl2 (200 uL), acetic anhydride (5 mg, 0.022 mmol) and pyridine (11 uL) was stirred at room temperature over night. The mixture was concentrated and dissolved in THF/water (1 mL) and LiOH (1 mg, 0.024 mmol) was added. The diacetylated intermediate was hydrolyzed at room temperature for 4 h. The crude product was purified by preparative HPLC (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/MeCN) to give 4.3 mg (56%) of the title compound. MS (ESI+) calcd for C18H16N2O5S2 404.050063, found 404.050323.
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5](=[N:12][NH:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>CO.C1COCC1.O>[CH2:5]([NH:12][NH:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cc(Cl)ccc1NN=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1NNCc1ccccc1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
A solution of sodium cyanoborohydride (780 mg) in methanol (20 ml) was added to a stirred solution of 2-(benzylidenehydrazino)-5-chlorobenzoic acid (2.7 g) in THF (20 ml) containing a few milligrams of the indicator Congo Red. A methanolic solution of hydrogen chloride was added dropwise until the indicator in the reaction solution turned blue. Stirring was continued for 15 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated to give 2-(2-benzylhydrazino)-5-chlorobenzoic acid as a solid (2.5 g) which was used without purification.