Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]1[N:5]=[CH:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[N:10]([CH3:19])[CH2:9][C:8]=12.N12CCCN=C1CCCCC2.O>CN(C)C=O>[C:3]([C:4]1[N:5]=[CH:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[N:10]([CH3:19])[CH2:9][C:8]=12)#[CH:2]
Reactant: CN1Cc2c(/C=C\Cl)ncn2-c2ccccc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
2.20 g (8 mmol) of 3-[(Z)-2-chlorovinyl]-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 145° for 6 hours together with 1.43 ml (9.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into water and extracted five times with methylene chloride. The organic extracts were washed five times with water, dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there was obtained 3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 191°-193°.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1C[O:30]CC1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][CH2:2][CH2:3][OH:30])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl) -1,3-oxazinan-2-one (1.19 g, 2.8 mmol) in THF (30 mL) was added BH3 THF (8.5 mL, I mol/L, 8.5 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then NaOH (1 mol/L, 6 mL) and H2O2 (5 mL) were added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (1.13 g, 92%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.OC1C=CC=C2C=1N=CC=C2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[I:1][C:2]1[CH:11]=[CH:10][C:9]([N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[O:13])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(I)ccc1I
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: C1COCCO1
Product: O=C(O)c1cc(-n2ccccc2=O)ccc1I
Temperature: 130 °C

Procedure:
A mixture of methyl 2,5-diiodobenzoate prepared above (1.04 g, 2.67 mmol), 2-hydroxypyridine 1-7 (0.254 g, 2.67 mmol), 8-hydroxyquinoline (0.077 g, 0.53 mmol) and K3PO4 (1.13 g, 5.33 mmol) in dioxane (8 mL) was degassed with Ar before being charged with CuI (0.101 g, 0.53 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give 2-iodo-5-(2-oxopyridin-1(2H)-yl)benzoic acid (0.220 g). MS 342.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][N:3]=1.[Br:21]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([Br:21])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(N)c2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(N)ncc2Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A flask was charged with ethyl 3-(2-aminopyridin-4-yloxy)-4-chlorobenzoate (5.50 g, 18.8 mmol) and acetic acid (50 mL), and bromine (0.943 ml, 18.4 mmol) was added. The reaction was stirred at ambient temperature for 30 minutes and then concentrated. The residue was purified by silica gel column chromatography, eluting with 20%-35% ethyl acetate in hexanes to give the desired product (4.20 g, 58.9% yield) as light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])COC)(=[O:13])=[O:12])=[C:7]([C:27]2[CH:28]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:13])=[O:12])=[C:7]([C:27]2[CH:32]=[N:31][CH:30]=[N:29][CH:28]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1-c1cncnc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1-c1cncnc1
Temperature: 75 °C
Yield: 87.2 %

Procedure:
To a solution of 17 (80.0 mg; 0.17 mmol) in tetrahydrofuran (5 mL) was added aqueous hydrochloric acid (5.0 mL; 10.0 mmol; 2N). The reaction mixture was heated at 75° C. for 4 hours, and then additional aqueous hydrochloric acid (3.0 mL; 6N) was added and the reaction mixture further heated at reflux for 4-5 hours. The reaction mixture was allowed to cool to room temperature and then extracted with ethyl acetate (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude clear oil was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to give the title product as a clear oil (64.0 mg).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[NH2:9][C@@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11]>>[NH2:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11]
Reactant: C[C@@H](N)C(=O)N1CCC[C@@H]1C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: C[C@H](N)C(=O)N1CCC[C@@H]1C(=O)O

Procedure:
By substituting D-proline for L-proline in the above example, a 70% diastereomeric excess mixture of D-alanyl-D-proline and L-alanyl-D-proline was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=O.CCN(C(C)C)C(C)C.[CH2:44]([O:51][C:52]1[CH:60]=[C:55]2[CH2:56][NH:57][CH2:58][CH2:59][N:54]2[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.[NH4+].[Cl-]>[CH2:44]([O:51][C:52]1[CH:60]=[C:55]2[CH2:56][N:57]([C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[CH:27]=3)=[O:31])[CH2:58][CH2:59][N:54]2[N:53]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: c1ccc(COc2cc3n(n2)CCNC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(F)c1)N1CCn2nc(OCc3ccccc3)cc2C1
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.159 g, 0.42 mmol) was added to a stirred solution of 3-fluorobenzoic acid (0.059 g, 0.42 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred for 5 minutes and then DIPEA (0.08 mL, 0.45 mmol) and 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.08 g, 0.35 mmol) were added. The mixture was stirred at room temperature for 16 hours, diluted with a saturated solution of NH4Cl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(benzyloxy)-5-[(3-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.055 g, 45% yield) as a white solid. C20H18FN3O2. 1H NMR (mixture of conformers 1/1; 500 MHz, CDCl3) δ ppm 3.87 (br. s., 1 H), 4.09 (br. s., 2 H), 4.20 (br. s., 1 H), 4.62 (br. s., 1 H), 4.84 (br. s., 1 H), 5.18 (s, 2 H), 5.44 (br. s., 0.5 H), 5.56 (br. s., 0.5 H), 7.14-7.21 (m, 2 H), 7.23 (dt, J=7.8, 1.2 Hz, 1 H), 7.29-7.34 (m, 1 H), 7.37 (t, J=7.4 Hz, 2 H), 7.40-7.47 (m, 3 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.Cl>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]3[S:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: ClCCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Reactant: c1c[nH]cn1
Agent: Cl
Product: C(=C/c1nc2ccccc2s1)\c1ccc(OCCCn2ccnc2)cc1
Yield: 39 %

Procedure:
The title compound was prepared in accordance with Example 28 starting with (F) of Example 28 (5.0 g, 15 mmol) and using imidazole in place of dibutylamine to produce 2.4 g (39% yield) of the title compound as the HCl salt, mp 231°-232° C. IR(KBr): 1595 cm-1. MS: 362(MH+). 1H NMR (CD3OH): δ 9.01 (s, 1H), 7.99-6.91 (m, 12H), 4.21 (t, J=5.2 Hz, 2H), 4.03 (t, J=5.3 Hz, 2H), 2.32 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[C:11]([CH:12]=[O:13])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:5])[CH3:4].O>C1COCC1>[C:3]([C:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.2 %

Procedure:
Sodium borohydride (50 mg, 1.3 mmol) was added to a solution of 2-[2-(3-tert-Butyl-4-formylpyrazol-1-yl)-acetylamino]-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (100 mg, 0.25 mmol) in THF (2 mL). The mixture was stirred for 1 h at ambient temperature. Water was added and the product extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using eluants EtOAc/heptane. The solid isolated was further purified by preparative reverse phase HPLC and passed down an SCX cartridge. The volatiles were blown off with nitrogen to give a white solid (2.4 mg, 0.61 μmol, 2%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].O=[C:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH:10]2[CH2:11][CH2:12]2)[N:1]=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: N#Cc1c(N)cccc1C1CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(C3CC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-cyclopropylbenzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a pale yellow solid (80%). MS 271 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](=[O:43])[C:27]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=3)([CH3:32])[CH2:28][O:29]2)=[CH:24][CH:23]=1>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][C:26]1([OH:43])[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:20][O:19][CH3:18])=[CH:23][CH:24]=2)[O:29][CH2:28][C:27]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:37][CH:38]=1)[CH3:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
4-(t-Butyldimethylsilyloxy)-1-butyne (1.17 g, 6.4 mmol) was dissolved in dry tetrahydrofuran (20 ml) under argon atmosphere, which was then cooled down to −78° C. n-Butyllithium (2.29 ml, 5.72 mmol, 2.5M solution in tetrahydrofuran) was slowly added dropwise thereto, and the mixture was stirred at −78° C. for 30 minutes. To this mixture was added dropwise 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-one (1.14 g, 3.18 mmol) dissolved in dry tetrahydrofuran (10 ml) at −78° C., and the resulting reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was cooled to 0° C. The reaction was quenched with water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (1.6 g, yield 93%) as a colorless oil.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][N:4]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(C1CCNCC1)N1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccncn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(C1CCN(c2ccncn2)CC1)N1CCN(Cc2ccccc2)CC1
Yield: 45.3 %

Procedure:
4-Chloropyrimidine hydrochloride (3.5 g) was added to a stirred suspension of 1-benzyl-4-[4-piperidylcarbonyl]piperazine (6.6 g), triethylamine (12.8 ml) and ethanol (120 ml). The mixture was heated under reflux for four hours and evaporated in vacuo to yield a treacle like substance. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was absorbed onto alumina and purified using dry flash chromatography eluting with increasingly polar mixtures of dichloromethane and methanol (1:0 to 98:2). The material obtained was triturated with diethylether to give 1-(benzyl)-4-[1 -(4-pyrimidinyl)-4-piperidylcarbonyl]piperazine (3.8 g, 45% yield), mp 107-108.5° C.;
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[C:19](Cl)(Cl)=[O:20].C1(C)C=CC=CC=1>C(Cl)Cl>[N:16]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:18][CH:17]=1)=[C:19]=[O:20]
Reactant: O=C(Cl)Cl
Reactant: COCCOCCOCCOc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCOCCOCCOc1ccc(N=C=O)cc1
Reaction time: 3 h

Procedure:
To a stirred 0° C. solution of 18 (0.59 g, 2.29 mmol) in DCM (23 mL) was added a 20% phosgene/toluene solution (2.42 mL). After stirring for 3 h the reaction mixture was concentrated under reduced pressure and carried on without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].C1CCNCC1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.C1(N=C=O)C=CC=CC=1>CC#N>[F:31][C:32]([F:42])([F:43])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)[CH2:15][CH2:16]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Solvent: O=C=Nc1ccccc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2cccc(OC(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-[{N-(3(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (19.9 mg, 0.058 mmol) in CH3CN (1.0 mL) and (piperidinomethyl)polystyrene (55 mg, 2.7 mmol base/g resin) were added to a solution of 3-(trifluoromethoxy)benzyl bromide (12.3 mg, 0.048 mmol) in CH3CN (1.0 mL). The reaction mixture was stirred at 60° C. for 2.5 h. Phenyl isocyanate (6.9 mg, 0.048 mmol) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford 1-{3-(trifluoromethoxy)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 927) (22.8 mg, 91%) as a pale yellow oil: The purity was determined by RPLC/MS (99%); ESI/MS m/e 518.1 (M++H, C24H26F6N3O3)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:9])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A solution of 3,4-dinitrobenzoic acid (200 mg, 0.943 mmol) and DMF (2 drops) in THF (7 mL) was treated with thionyl chloride (0.14 mL, 224 mmol) and then heated at reflux for 2.5 h. The mixture was cooled to 0° C. and triethylamine (286 mg, 1.883 mmol) was added over 25 min while keeping the internal temperature at 0° C. Morpholine (164 mg, 1.883 mmol) was added. The mixture was stirred overnight and allowed to warm to ambient temperature. Purification by flash chromatography afforded the title compound (150 mg). 1H NMR (400 MHz, CD3OD): δ 8.36 (s, 1H), 8.10 (d, 1H, J=8.8 Hz), 7.28 (d, 1H, J=9.2 Hz), 3.79 (m, 4H), 3.16 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:25][CH2:26][OH:27]>CN(C=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:25][CH2:26][OH:27])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)cc1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 12.8 %

Procedure:
To a solution of 4-(4-nitrophenoxy)quinolin-7-ol (2.82 g, 10 mmol) in DMF (20 mL) was added KOH pellets (1.12 g, 20 mmol) and 2-bromoethanol (1.87 g, 15 mmol) at room temperature. The reaction was then warmed up to 45° C. and stirred for 12 hours. The mixture was then concentrated in vacuo and the residue was purified by a column chromatography on silica gel (EtOAc/PE=1:1) to give the title compound as a pale yellow solid (417 mg, 12.8%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[NH:17][CH:16]=[CH:15][C:12]3=[N:13][CH:14]=2)O1.[NH2:19][C:20]1[C:29]2[C:24](=[C:25](Br)[C:26]([CH3:30])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:32]([NH2:34])=[O:33]>>[NH2:19][C:20]1[C:29]2[C:24](=[C:25]([C:9]3[CH:10]=[C:11]4[NH:17][CH:16]=[CH:15][C:12]4=[N:13][CH:14]=3)[C:26]([CH3:30])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:32]([NH2:34])=[O:33]
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1cnc2cc[nH]c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H), 6.84 (br s, 1 H), 6.93 (br s, 1 H), 7.85 (d, J=8.59 Hz, 1 H), 8.15 (br s, 1 H), 8.27-8.30 (m, 1 H), 8.35 (s, 1 H), 8.54 (d, J=8.59 Hz, 1 H), 8.58 (s, 1 H), 8.71 (br s, 1 H), 8.76 (s, 1 H); ESI-MS m/z [M+H]+ 319.2.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH2:29])([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:66])([C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:66])[C:56]([F:64])([F:65])[C:57]([F:63])([F:62])[C:58]([F:61])([F:59])[F:60])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Product: C[C@]12C[C@H](CCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][CH2:3][O:4][Si:9]([C:6]([CH3:8])([CH3:7])[CH3:5])([CH3:11])[CH3:10]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-bromo-ethanol (12.5 g, 0.1 mol) and TEA (11.2 g, 0.11 mol) in CH2Cl2 (40 mL), TBSCl (15.8 g, 0.105 mol) and DMAP (0.122 g, 1 mmol) were added. The reaction mixture was stirred at room temperature for 12 h, washed (10 mL 2M HCl, 10 mL H2O), dried (Na2SO4) and concentrated to give the desired product as colorless oil. 1H NMR (CDCl3): δ 3.88 (m, 2H), 3.39 (m, 2H), 0.89 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: COC([C@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OC)=[O:13])[CH2:7][C@H:6]1[C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=O.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[CH2:18]([N:17]([CH2:20][CH3:21])[C:16]([C@@H:6]1[C@H:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]2=[O:13])[CH2:7]1)=[O:22])[CH3:19]
Reactant: CCN(CC)C(=O)[C@@H]1CN(CC(=O)OC)CC[C@@H]1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of 12 (159 g, 0.503 mole) in toluene (700 ml) was added dropwise over a period 2.5 hours to a solution of potassium t-butoxide (169 g, 1.51 mole) in toluene (1.9 L) at 110° C. under a nitrogen condition. The mixture was heated at reflux for 1 hour and cooled down to room temperature. Water (400 ml) was added then the layers were heated at reflux for 2 hours. After the organic layer was separated, the aqueous layer was neutralized and extracted with EtOAc for 15 hours with continuous extraction apparatus. The combined extracts were dried over MgSO4 and concentrated down. Recrystallization from EtOH gave 13 (34.6 g, 31%) as a colorless crystal. The stereochemistry was determined by X-Ray analysis, 13C and NMR.