Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1>>[CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and. 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.60-1.75 (m, 11 H) 1.84-2.09 (m, 5 H) 2.19 (s, 3 H) 2.80 (d, J=11.1 Hz, 2 H) 3.26 (s, 3 H) 3.60-3.83 (m, 3 H) 3.94 (s, 3 H) 4.78 (t, J=8.1 Hz, 1 H) 7.35-7.60 (m, 2 H) 7.80 (s, 1 H) 8.08 (d, J=7.6 Hz, 1 H) 8.16 (s, 1 H) 8.32 (d, J=8.3 Hz, 1 H). Melting point: 149-153° C. [M+H] calc'd for C29H40FN7O3, 554; found 554.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>CN(C=O)C>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:37]([O:39][CH3:40])=[O:38])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.0 mg, 0.0679 mmol), N,N-diisopropylethylamine (59.1 μL, 0.340 mmol) and DMF (1.00 mL) was treated with methyl chloroformate (5.25 μL, 0.0679 mmol) and stirred at rt for 1 h prior to semi-preparative HPLC to afford the isolation of the title compound. 1H NMR (400 MHz, CD3OD) ppm: 8.32 (br. s., 1H), 7.58-7.66 (m, 2H), 7.46 (d, 1H, J=8.1 Hz), 7.14-7.22 (m, 1H), 7.00-7.12 (m, 2H), 6.73 (s, 1H), 4.26 (d, 2H, J=12.9 Hz), 3.71 (s, 3H), 3.33-3.37 (m, 1H), 2.9-3.17 (m, 2H), 1.85-2.06 (m, 4H); MS (ES+): m/z 391.06 [MH+].
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].OS(O)(=O)=O.[O:10]=[C:11]1[CH2:16][CH:15]2[CH:17]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)[CH:12]1[CH2:13][CH2:14]2.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:10]=[C:11]1[NH:1][CH2:16][CH:15]2[CH:17]([C:18]3[NH:19][C:20]4[N:21]([CH2:32][CH2:33][CH3:34])[C:22](=[O:31])[N:23]([CH2:28][CH2:29][CH3:30])[C:24](=[O:27])[C:25]=4[N:26]=3)[CH:12]1[CH2:13][CH2:14]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCn1c(=O)c2[nH]c(C3C4CCC3C(=O)C4)nc2n(CCC)c1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2nc(C3C4CCC3C(=O)NC4)[nH]c2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a solution of NaN3 (65 mg) in CHCl3 (2 ml) was added H2SO4 (0.5 ml). The resulting solution was cooled to 0° C. 8-(2-Oxo-bicyclo[2.2.1]hept-7-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (173 mg) in CHCl3 (3 ml) was added. The resulting solution was stirred at room temperature for 3 hrs. The reaction mixture was poured over ice and neutralized with NaHCO3, extracted with ethyl acetate (3×25 ml). The combined extract was dried over MgSO4, filtered, and concentrated. The crude product was purified by recrystallization from MeOH. Yield 155 mg. Mass (ES+ 360).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:28])=[C:20]([C:23](OCC)=[O:24])[CH2:21][CH3:22])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:23](=[O:24])[C:20]([CH2:21][CH3:22])=[C:19]([CH3:28])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCc1c(C)[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methyl-1-butenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-ethyl-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 176°-178° C.,
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:21]([C:22](O)=[O:23])[CH:20]=1.[BH4-].[Na+]>ClCCl.O>[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: COC(=O)c1cc(F)cc(C(=O)O)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
Triethylamine (2.2 ml, 16.0 mmol) and isobutyl chloroformate (1.0 ml, 8.0 mmol) were added to an ice-cooled solution of 5-fluoro-isophthalic acid monomethyl ester (1.3 g, 6.7 mmol) in dichloromethane (20 ml) and then warmed to room temperature. After stirring for 2 h, the reaction mixture was filtered and concentrated. The residue was re-dissolved tetrahydrofuran (10 ml) and then sodium borohydride (1.1 g, 29.02 mmol) in water (3 ml) was added drop-wise. After 1 h, the reaction was quenched with methanol and then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash column chromatography on silica gel using 30% ethyl acetate in hexanes afforded 667 mg (54%) of 3-fluoro-5-hydroxymethyl-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3), δ (ppm): 7.82 (s, 1H), 7.63 (d, 1H), 7.32 (d, 1H), 4.76 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1CCCC1=O.F[C:9]1[C:14]2[CH2:15][C:16](=[O:26])[C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[S:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.[Cu](C#N)C#N.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:1]([C:9]1[C:14]2[CH2:15][C:16](=[O:26])[C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[S:19][C:13]=2[CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: COc1ccc2c(c1)C(=O)Cc1c(F)cccc1S2
Reactant: CN1CCCC1=O
Agent: N#C[Cu]C#N
Agent: [Cu+2]
Agent: N
Solvent: O
Product: COc1ccc2c(c1)C(=O)Cc1c(C#N)cccc1S2
Reaction time: 14 h

Procedure:
To 50 ml of N-methylpyrrolidone were added 5.8 g of 9-fluoro-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]-thiepin, 5.4 g of copper cyanide and 0.2 g anhydrous copper sulfate, and the resulting mixture was heated with stirring at 230°-240° C. for 14 hours. After cooling, to the reaction mixture were added 200 ml of 28% aqueous ammonia and 320 ml of water, and the resulting mixture was extracted with benzene. The aqueous and benzene layers were filtered through celite. The collected benzene layer was washed with water several times, diluted hydrochloric acid and then water, which was dried over anhydrous sodium sulfate. The solvent was evaporated to obtain about 6 g of residue which was chromatographed on silica gel. 1.0 g of the starting material was recovered from benzene/chloroform (1/1) eluate and there was obtained from chloroform eluate 9-cyano-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]-thiepin, which was washed with ethanol to give 2.1 g of pale yellow needles having a melting point of 188°-189° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27](O)=[O:28].[NH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:32]1([CH2:31][NH:30][C:27]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[C:19]([C:21]6[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=6)[S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:28])[CH2:34][CH2:33]1
Reactant: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Reactant: NCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NCC1CC1
Yield: 81.2 %

Procedure:
This material was prepared from the reaction of 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylic acid 117b (70 mg, 0.166 mmole), (aminomethyl)cyclopropane (43 μL, 0.50 mmole) and diisopropylethylamine (58 μL, 0.33 mmole), and HBTU (94 mg, 0.25 mmole) in a manner similar to that previously described for example 117 to afford a pale yellow solid (64 mg, 53%). 1H NMR (DMSO-d6, 300 MHz) δ8.61 (1H, d, J=5.46 Hz), 8.49 (1H, t, J=5.65 Hz), 8.07 (1H, s), 7.99 (1H, d, J=2.26 Hz), 7.85 (1H, d, J=8.67 Hz), 7.63 (1H, s), 7.37 (1H, s), 7.36 (1H, dd, J=2.4, 8.67 Hz), 6.81 (1H, d, J=5.65 Hz), 4.01 (3H, s), 3.20 (2H, t, J=6.31 Hz), 2.62 (3H, s), 1.08 (1H, m), 0.47 (2H, m), 0.27 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(N)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred mixture of 2-chloro-4-methyl-6-nitroaniline (7.39 g, 39.7 mM) and concentrated sulfuric acid (6.2 mL) in absolute ethanol (50 mL) at 0°-5° C. was slowly added a solution of sodium nitrite (6.85 g, 99.3 mM) in water (6 mL). The temperature of the reaction mixture was not allowed to exceed 5° C. during the addition. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 hr and then at reflux until the evolution of gas from the reaction mixture ceased. The reaction mixture was allowed to cool and was concentrated. The residue was slurried with ether and then filtered to remove the solids. The liltrate was concentrated and the residue chromatographed (eluant: diethyl ether/hexane; 1/9) to provide (6.25 g, 92%) the title compound as a yellow crystalline solid, mp 60.5°-61° C.; MS(CI): 172 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2I.[Cl:18][C:19]1[S:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:22][N:23]=1>[Cu]I.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:21]1[S:20][C:19]([Cl:18])=[N:23][CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(Cl)s1
Reactant: Brc1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Clc1ncc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)s1

Procedure:
The title compound was prepared analogously to compound 30a, using 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.56 g, 6.29 mmol), 2-chloro-5-(tributylstannyl)thiazole (2.955 g, 7.23 mmol, Synthonix), CuI (0.12 g, 0.630 mmol) and Pd(PPh3)4 (0.74 g, 0.640 mmol). Purification by flash chromatography (Isco, (120 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:99) gave 2.12 g (85%) of a white amorphous solid. m/z: 397.8, 399.8 [M+1].
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:7]([NH:1][C@H:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)N[C@H](C)C(=O)O

Procedure:
D-alanine (20 mmol) and hexanoyl chloride (22 mmol) were reacted using the method as described in Example 5 Part A to give the title compound as a white crystalline material (2.45 g, 65.5%) after recrystallization from isopropyl ether (20 ml), m.p. 82°-95° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:11]([C:17](=[O:19])[CH3:18])=[CH:12][C:13]=1[C:14](=[O:16])[CH3:15])[NH:8][CH2:9][CH3:10])C=C.CN1C(=O)[CH2:24][CH2:23][CH2:22]1>C(O)C.[Pd]>[C:17]([C:11]1[CH:12]=[C:13]([C:14](=[O:16])[CH3:15])[C:5]([OH:4])=[C:6]([CH2:22][CH2:23][CH3:24])[C:7]=1[NH:8][CH2:9][CH3:10])(=[O:19])[CH3:18]
Reactant: C=CCOc1cc(NCC)c(C(C)=O)cc1C(C)=O
Reactant: CN1CCCC1=O
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc(C(C)=O)c1NCC
Temperature: 25 °C
Yield: 63 %

Procedure:
The product of step (b) (0.013 mole) was heated in NMP (25 ml) at reflux under nitrogen for 1 hour. After cooling to room temperature, the mixture was diluted with ethanol (25 ml), and hydrogenated over 5% Pd/C at 15-20 psi for 21/2 hours. After filtration, the mixture was poured into water, the grey solid isolated by filtration, and recrystallised from ethanol to give the title compound. Yield 63%, mp 114°-115° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[Na+].II.[CH2:21]([C:24](=[CH2:28])[C:25]([OH:27])=[O:26])[CH2:22][CH3:23].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.ClCCl>[CH2:21](/[C:24](=[CH:28]\[S:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:8])=[CH:14][CH:13]=1)(=[O:17])=[O:16])/[C:25]([OH:27])=[O:26])[CH2:22][CH3:23]
Reactant: O=C(c1ccncc1)c1ccc(S(=O)[O-])cc1
Reactant: C=C(CCC)C(=O)O
Agent: II
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC/C(=C\S(=O)(=O)c1ccc(C(=O)c2ccncc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Sodium 4-(pyridine-4-carbonyl)benzenesulfinate (3.33 g, 14.04 mmol) was dissolved in water (60 ml). This solution was shaken with iodine (3.56 g, 34.29 mmol) in dishloromethane (40 ml). The dichloromethane layer turned from deep pink to orange. The dishloromethane layer was dried over magnesium sulfate and filtered into a flask containing 2-propylacrylic acid (0.8 g, 7.02 mmol). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (4.0 ml, 28.08 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. The mixture was acidified to pH 4 by addition of 10% citric acid. The layers were separated and the product was extracted with 2M sodium hydroxide (3×50 ml). The combined aqueous phase was washed with ethyl acetate (50 ml), the acidified to pH 4 with citric acid. The product was extracted into ethyl acetate (2×50 ml), then back into 1M hydrochloric acid (100 ml). The aqueous layer was washed with ethyl acetate (2×50 ml), then solid sodium hydrogen carbonate was added to pH 4. The product was extracted into dichloromethane (2×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound (0.60 g, 24%).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([OH:18])=[O:17].C(O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([O:18][CH2:1][CH3:2])=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 16.09 g (78 mmol) of 1,3-dicyclohexylcarbodiimide (Aldrich) in 100 ml methylene chloride was added a suspension of 15.4 g (71 mmol) of 4-carboxybenzylbromide in 100 ml methylene chloride and then 4.9 g (106.5 mmol) of absolute ethanol and 0.81 g (7.1 mmol) of 4-dimethylaminopyridine. A further 50 ml of methylene chloride was added to the reaction mixture and mixture heated at reflux for 2 h. The mixture was allowed to cool to room temperature and the resultant white precipitate removed by filtration. The filtrate was washed with water, dried (MgSO4) and then concentrated in-vacuo to give the title compound as a colorless oil which crystallized on standing. PMR (CDCl3): δ 1.39 (3H, t, J~7.2 Hz), 4.38 (2H, q, J~7.2 Hz), 4.50 (2H, s), 7.45 (2H, d, J~7.7 Hz), 8.03 (2H, d, J~7.7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].Cl.[O:15]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1ccccc1Oc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3Oc3ccccc3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-phenoxy-benzylamine hydrochloride (151 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-phenoxy-benzylamino)-2H-phthalazin-1-one: 81 mg (37.0%): m/z (M+H)=378. 1H-NMR (DMSO-d6) δ: 12.77 (s, 1H), 8.34 (d, 1H), 8.03 (m, 1H), 7.82 (m, 3H), 7.71 (m, 1H), 7.56 (m, 3H), 7.42 (m, 2H), 7.33 (dd, 1H), 7.20 (s, 1H), 4.84 (d, 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[C:37](=[O:38])[N:36]([CH3:39])[C@@H:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:34](=[O:44])[NH:33][C@@H:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[C@@H:26]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:25](=[O:56])[NH:24][C@@H:23]([CH2:57][O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[C:22](=[O:63])[N:21]([CH3:64])[C@@H:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][C@H:17]([C:70]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[O:71])[CH2:16][S:15][CH2:14][C:13](=[O:78])[N:12]([CH3:79])[C@@H:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH:84]OS([O-])=O.[K+].CS(C)=O>CO>[CH2:1]([C@H:8]1[C:37](=[O:38])[N:36]([CH3:39])[C@@H:35]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:34](=[O:44])[NH:33][C@@H:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[C@@H:26]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:25](=[O:56])[NH:24][C@@H:23]([CH2:57][O:58][C:59]([CH3:60])([CH3:62])[CH3:61])[C:22](=[O:63])[N:21]([CH3:64])[C@@H:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][C@H:17]([C:70]([N:72]2[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77]2)=[O:71])[CH2:16][S:15](=[O:84])[CH2:14][C:13](=[O:78])[N:12]([CH3:79])[C@@H:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N2CCCCC2)CSCC(=O)N(C)[C@@H](C)C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N1C
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N2CCCCC2)CS(=O)CC(=O)N(C)[C@@H](C)C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N1C
Yield: 89.3 %

Procedure:
(5S,8S,11S,14S,20S,23S,26S,29R)-8-Benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonone (Compound P-109) (9.5 mg, 8.11×10−3 mmol) was dissolved in methanol (0.5 ml), and water (0.25 ml) was added. The solution was cooled in an ice bath with stirring, and oxone (5.5 mg, 8.92×10−3 mmol) was added. The reaction mixture was stirred under ice-cooling for 25 minutes, and DMSO (80 μl) was then added. The mixture was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=60/40→0/100) to afford (5S,8S,11S,14S,20S,23S,26S,29R)-8-benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonone 1-oxide (Compound P-114) (8.6 mg, 90%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17](I)[C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[C:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C(I)[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C(C)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1.4 g (3 mmol) of 17α-acetoxy-2-iodo-1α-methyl-androst-4-en-3-one of example 11 and 0.443 g (6 mmol) of anhydrous lithium carbonate are stirred in 6 ml of dimethylformamide for 1 hour at 120° C. under nitrogen atmosphere. After cooling, it is added to water and extracted with ethyl acetate. The ethyl acetate solution is dried on sodium sulfate and then concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After concentration by evaporation of the fractions, 0.95 g (92% of theory) of 17β-acetoxy-1-methyl-androsta-1,4-dien-3-one of melting point 173° C. is obtained.