Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([C:30]2[CH:34]=[CH:33][O:32][N:31]=2)[CH2:14][C:15]([N:17]2[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])=[CH:9][CH:8]=1.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH2:22]([C@H:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:37]=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)[C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reaction time: 16 h
Yield: 106.6 %

Procedure:
To a solution of substituted aniline 27.3 (0.050 g, 0.100 mmol) in DCM (2 mL), was added TEA (0.10 mmol) and pivaloyl chloride (0.0124 mL, 0.100 mmol). The reaction mixture was stirred for 16 hours and then concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 20 to 60% EtOAc:hexanes) to give 30.1 (62 mg). MS ESI (pos.) m/e: 582.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:18][N:17]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Agent: Cl
Solvent: CCO
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-(5-bromo-3-methylpyrid-2-yl)butylamine (11.79 g) and 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (4.57 g) was refluxed in ethanol (100 ml) for 8 hours. The solvent was removed in vacuo, the residue was dissolved in water (100 ml) and then extracted with chloroform (100 ml). The chloroform extract was chromatographed on silica eluted with 5% v/v methanol in chloroform followed by recrystallisation from chloroform/hexane to give the title compound as a yellow solid, m.p. 82°-84° C.
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:1]1([S:7][CH2:8][Si:11]([Cl:13])([Cl:12])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCSc1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CSc1ccccc1
Reaction time: 12 h
Yield: 44.6 %

Procedure:
As in Example 1, phenylthiomethyl chloride (2.97 g, 0.0187 mol)), trichlorosilane (7.61 g, 0.0562 mol) and tetrabutylphosphonium chloride (2.97 g, 0.0187 mol) were put in a 50 mL stainless steel tube under nitrogen atmosphere. The reaction chamber was closed with a cover and the reaction was carried out at 120° C. for 12 hours. This reaction mixture was distilled under low pressure to give 2.15 g of (phenylthiomethyl)trichlorosilane in 44.5% yield.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)[CH3:4].[F:14][C:15]([F:42])([S:38]([OH:41])(=[O:40])=[O:39])[C:16]([F:37])([F:36])[C:17]([F:35])([F:34])[C:18]([F:33])([F:32])[C:19]([F:31])([F:30])[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23]>C(O)C>[F:42][C:15]([F:14])([S:38]([O-:41])(=[O:40])=[O:39])[C:16]([F:36])([F:37])[C:17]([F:35])([F:34])[C:18]([F:32])([F:33])[C:19]([F:31])([F:30])[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23].[CH3:1][NH2+:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=1)[CH3:4]
Reactant: CNC(C)c1ccc(C(C)C)cc1
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCO
Product: C[NH2+]C(C)c1ccc(C(C)C)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
The perfluoro-octyl sulphonate salt was prepared by mixing a solution of N-methyl-1-(4-isopropylphenyl) ethylamine (17.6 g) in ethanol (20 ml) with a solution of perfluoro-octylsulphonic acid (50 g) in ethanol (150 ml). The ethanol solution was evaporated under reduced pressure and the solid residue was recrystallised from chloroform as soft colourless plates of N-methyl-1-(4-isopropylphenyl) ethylammonium perfluoro-octylsulphonate (60 g). (Found: C 33.05; H 2.43; N 2.09%. C20H20F17NO3S requires: C 35.4; H 2.98; N 2.07%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]Br)[C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[NH2:14][C@@H:15]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][N:14]([C@@H:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1ncc(Br)cc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)cnc2C1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (500.0 mg, 1.618 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (482.8 mg, 1.618 mmol) and N,N-diisopropylethylamine (0.564 mL, 3.24 mmol) in 1-butanol (10.0 mL) was stirred at 120° C. for 2 h under microwave. Purification by combi-flash chromatography gave 0.48 g (61% yield) of the desired product. LC-MS found: 494.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C>C(O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:20]3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCCN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NN=Cc1ccc(C2=NOC3(CCN(CCCCC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.4 g (0.946 mmol) of the ester from Example 18 in 6 ml ethanol were added 1.2 ml 2 N aqueous sodium hydroxide solution. The mixture was stirred at room temperature over night, and stirring was continued for another 30 min after addition of another 0.2 ml sodium hydroxide. It was brought to pH 5 with diluted acetic acid, and the precipitate of the title compound was filtered with suction. After stirring with a small amount of water for 30 min, it was filtered again, washed with water and with ethanol, and dried in vacuo at 60° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([CH3:27])=[C:15]([CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:16]=3[CH3:17])[C:9](=[O:28])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:29]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])#[CH:30].Cl>>[CH3:17][C:16]1[C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[C:14]([CH3:27])[NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([C:29]#[CH:30])[CH:32]=3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:28]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Cl)c32)c(C)c1CCCN1CCOCC1
Reactant: C#Cc1cccc(N)c1
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3c2C(=Cc2[nH]c(C)c(CCCN4CCOCC4)c2C)C(=O)N3)c1
Yield: 7 %

Procedure:
The title compound (7% yield) was prepared from 4-chloro-5-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3-ethynylaniline according to the procedure described for Example 12 without the conversion to HCl salt. MS 483.3 [M++1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([N+:13]([O-:15])=[O:14])=[CH:5]2.C[CH2:17][O:18][C:19]([CH3:21])=O.Cl[CH:23](Cl)[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C@@:6]1([N+:13]([O-:15])=[O:14])[CH2:23][CH:24]=[C:19]([O:18][CH3:17])[CH2:21][C@@H:5]21
Reactant: CCOC(C)=O
Reactant: O=c1oc2ccc(F)cc2cc1[N+](=O)[O-]
Reactant: CC(Cl)Cl
Product: COC1=CC[C@]2([N+](=O)[O-])C(=O)Oc3ccc(F)cc3[C@@H]2C1
Temperature: 25 °C
Yield: 63 %

Procedure:
6-fluoro-3-nitro-2H-chromen-2-one (8.50 g, 40.66 mmol) and 2,2-dimethoxy-1-butene (10.2 g, 120 mmol) were stirred together in dichloroethane (100 mL) at reflux under a N2 atmosphere for 1 h. TLC (25% EtOAc in hexanes) indicated reaction was complete, so reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The resulting brown solid was purified by flash chromatography on silica gel to afford the title compound as an off-white solid (7.50 g, 63%); MS (APPI) m/z=294 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:34]=[CH:35][C:36]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:37][CH:38]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: C#CCN1CCCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCCC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-Propargylpyrrolidine (300 mg, 2.75 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (500 mg, 0.91 mmol) in a mixture of tetrahydrofuran (8 mL) and triethylamine (8 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL) and the resulting mixture was washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene-chloroform/ether 2:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]-acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: BrCCCOc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and 1-methylpiperazine (100 mg, 1.02 mmol) in CH3CN (6 mL) was added Cs2CO3 (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (280 mg, 75% yield) as a yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]3([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20][CH2:19]3)=O)[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2([CH2:16][N:12]3[CH2:13][CH2:14][CH2:15][CH:10]([CH2:8][NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11]3)[CH2:19][CH2:20][CH2:21]2)=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccccc1)C1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(CN3CCCC(CNc4ccccc4)C3)CCC2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A solution of 202 (0.504 mmol, 200 mg) in Toluene (2 mL) at 0° C. was treated with 3.0 M Red-Al (3.5 equiv, 1.76 mmol) under Ar. The reaction mixture stirred for 12 h and returned to 25° C. The reaction mixture was then cooled to 0° C., quenched with 10% aqueous NaOH and extracted with EtOAc (3×25 mL). The organics were dried with NaCl(sat) and NA2SO4 (s). The reaction mixture was purified by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, 2:1 hexane-EtOAc) which provided 203 (170 mg, 186 mg theoretical, 91%) as a colorless oil: Rf 0.61 (SiO2, 2:1 hexane-EtOAc); LRMS m/z 368 (M+, C23H29ClN2, requires 368).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[Li]CCCC.[CH2:18]1[O:20][CH2:19]1.O>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH2:18][CH2:19][OH:20]
Reactant: C1CO1
Reactant: Cn1cnc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1CCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
A solution of 674 mg (4.26 mmol) of 1-methyl-4-phenylimidazole (Kashima, C.; Harada, Y.; Hosomi, A. Heterocycles 1993, 35, 433) in 8.5 mL of THF at −78° C. was treated with 1.9 mL (4.69 mmol) of a 2.5 M nBuLi in hexanes solution. After stirring for 10 min, 1.1 mL (21.3 mmol) of ethylene oxide was added. The reaction was stirred for min then warmed to 25° C. and stirred for 1 h. Upon cooling to 0° C., 1.1 mL (21.3 mmol) of ethylene oxide was added, and the reaction was warmed to 25° C. and stirred overnight. The reaction was poured into H2O and extracted with Et2O. The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using EtOAc/MeOH (95:5), and the collected product was recrystallized from CH2Cl2/EtOAc to give 178 mg (21%) of title compound as a white solid: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C([O-])(=O)C.[Na+]>O.CC(C)=O>[F:24][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc2)S1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
7 g (18.7 mmole) of 4-[2-(4-formylphenoxy)ethyl]phenyl trifluoromethanesulfonate, 2.74 g (23.4 mmole) 2,4-thiazolidinedione and 3.8 g (46.8 mmole) sodium acetate were mixed and heated under vacuum to 140° C. when it melted. It was kept at 140° C. for 20 minutes and thereafter taken off the heat, water:acetone (2:1) was added, the formed crystals were filtered off and recrystallization in dichloromethane gave 2.09 g (yield 24%) 5-(4-[2-(4-trifluoromethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22](Cl)=[O:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30].CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[O:30]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][NH:27][C:22]([C:20]1[CH:19]=[N:18][C:14]2[O:15][CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13]=2[CH:21]=1)=[O:23]
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reactant: NCC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (100 mg, 0.246 mmol), in THF (5 mL) was added 2-amino-1-phenylethanone (34.9 mg, 0.258 mmol), and DIPEA (0.086 mL, 0.492 mmol). The reaction was stirred for 2 hours at room temperature. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (5 mL). The aqueous layer was back extracted with EtOAc (2×5 mL). Combined the organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide N-(2-oxo-2-phenylethyl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (115 mg, 0.246 mmol, 93%) as a light brown oil. The material was used without further purification. LCMS (+ESI) m/z=506.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:30]([C:29]4[CH:33]=[CH:34][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)=[O:31])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). 4-Cyanobenzoyl chloride (47.84 mg; 0.29 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 22 (40 mg, 45% yield) as a pale yellow solid. LC-MS (M+H=337, obsd.=337).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:27].[K+]>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C#N)cc3)ccc2C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Reaction time: 72 h
Yield: 45.4 %

Procedure:
Combine 6-(4-Cyano-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.93, 5.51 mmol), t-butyl alcohol (50 ml), and KOH (1.56 g, 27.6 mmol). After the reaction stirs for 72 hours at room temperature, concentrate under reduced pressure then add ethyl acetate. Wash the ethyl acetate with a brine solution and dry the organic layer over Na2SO4. After concentrating the organic layer under reduced pressure, the reaction affords 1.93 g, 2.50 mmol (95% yield) of the title compound as a white solid: 1H NMR (500 MHz, CDCl3); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H, s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.7-7.9 (2H, m); TLC Rf=0.5 2:1 Hexanes:Ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38][Cl:39].C(#N)C>C(OC(C)C)(C)C>[Cl-:39].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:38][O:37][C:36]([O:40][CH:41]([CH3:43])[CH3:42])=[O:44])[CH:32]=[N:31]1
Reactant: CC(C)OC(=O)OCCl
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: CC(C)OC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4cnnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 6 h
Yield: 16.7 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.5 g), chloromethyl isopropyl carbonate (3.17 g) and acetonitrile (1 ml) was stirred for 6 hours at 100° C. After having been cooled, the mixture was diluted with diisopropyl ether (10 ml). The resulting powder was collected by filtration. The powder was subjected to silica gel chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=10/1→acetone/ethanol=5/1). The solvent was distilled off, and the residue was crystallized from ethanol/acetone to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-(isopropoxycarbonyloxy)methyl-1H-1,2,4-triazolium chloride (Compound 18, 110 mg) as white powdery crystals.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C(=O)(O)[O-].[Na+].[Br:27][CH2:28][C:29](Cl)=[O:30]>C1C=CC=CC=1>[Br:27][CH2:28][C:29]([O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3)=[O:30]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)CBr

Procedure:
To a solution of 2.884 g (0.01 mol) of testosterone in 30 ml of dry benzene was added 1.008 g (0.012 mol) of sodium bicarbonate; then, while stirring, there were introduced dropwise 1.888 g (0.012 tool) of bromoacetyl chloride over a 5 minute period. The reaction mixture was then stirred under reflux for 6 hours until no testosterone could be traced by TLC. (Plates of Silica Gel G and a CHCH3 /CH3OH system were used.) The inorganic residue was filtered while hot, the filtrate was evaporated in vacuo and the residue was recrystallized from methanol, m.p. 144°-145° C., yield 3.2 g (78%). IR (KBr) 1735 (C=O), 1660 (C=O) cm-1. PMR as expected. The product has the formula: ##STR1506##