Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]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:8]2=3)[CH2:6][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.[NH2:58][N:59]1[CH2:64][CH2:63][N:62]([C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[O:66])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][N:59]5[CH2:60][CH2:61][N:62]([C:65]([O:67][CH2:68][C:69]6[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=6)=[O:66])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCN(C(=O)OCc3ccccc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-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 benzyl 4-aminopiperazine 1-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:4]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].[Na].CC(C)([O-])C>CO>[CH2:19]([NH:23][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CCCCN
Agent: CC(C)(C)[O-]
Agent: [Na]
Solvent: CO
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 42.5 °C

Procedure:
Mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100 grams), methanol (1 L), n-butyl amine (200 ml) and sodium, tertiary butoxide (74 grams) was heated to 40-45° C. and stirred up to completion of the reaction. Distilled off the reaction mixture completely under reduced pressure and water (300 ml) was added to it at 25-30° C. The reaction mixture was cooled and acidified with aqueous acetic acid. The reaction mixture washed with cyclohexane and product from aqueous layer was extracted into methylene chloride. The organic layer was washed with saturated sodium chloride solution and the solvent from it was distilled off under reduced pressure to get the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][N:4]=1.[CH3:18]I>>[CH3:18][N:4]1[CH:5]=[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:7]=[CH:8][C:3]1=[O:2]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CI
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Temperature: 80 °C

Procedure:
A mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (235 mg, 1.00 mmol) and CH3I (426 mg, 3.00 mmol) was heated at 80° C. for 3 hours. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, and evaporated to dryness to afford 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one that was directly used in next step without further purification.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]([F:14])[CH:10]=[C:11]([Br:13])[CH:12]=1.C1C[O:18][CH2:17]C1>>[Br:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([F:14])[CH:10]=1)[CH:17]=[O:18]
Reactant: C1CCOC1
Reactant: Fc1cc(Br)cc(Br)c1
Agent: CC(C)[Mg]Cl
Product: O=Cc1cc(F)cc(Br)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
step 1—To a solution of iso-propylmagnesium chloride in THF (500 mL of a 2M solution in THF, 1.0 mol) and THF (200 mL) was added a solution of 3,5-dibromofluorobenzene (25; 200 g, 0.79 mol) in THF (100 mL) while maintaining the temperature at ca. 0 C. After rinsing with THF (3×20 mL) the mixture was aged for 2 h at ca. 0° C. and then warmed to ca. 20° C. and aged for 0.5 h. The reaction was sampled by HPLC and then cooled to ca. 0° C. DMF was added over 0.5 h while maintaining the temperature at ca. 0° C. The mixture was aged 1.5 h at ca. 0° C. and then warmed slowly to ca. 20° C. overnight. After sampling by HPLC, the mixture was diluted with heptane (200 mL) and then with a mixture of con HCl (120 mL) diluted to 360 mL with water. Con HCl (50 mL) was added to adjust the pH to <7. The organic phase was separated, washed with water (400 mL) and evaporated to dryness to afford 160.8 g (100.5%) of 28 as a yellow oil which solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[O:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1)[Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCl
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: CC(C)(C)[Si](C)(C)OCCCCCn1nc(I)c2cc(F)ccc21
Yield: 79 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and (5-chloropentoxy)tert-butyldimethylsilane in 79% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.06 (6H, s), 0.90 (9H, s), 1.34-1.37 (2H, m), 1.50-1.55 (2H, m), 1.90-1.94 (2H, m), 3.55 (2H, t, J=6.4 Hz), 4.37 (2H, t, J=7.2 Hz), 7.10 (1H, dd, J=2.0, 8.0 Hz), 7.19 (1H, td, J=2.4, 8.8 Hz), 7.432 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.[CH:39]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][N:41]([C:48](=O)[CH2:49]Cl)[CH2:40]2>>[CH:43]12[CH2:46][CH2:47][CH:39]([CH2:45][CH2:44]1)[CH2:40][N:41]([CH2:48][CH2:49][O:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:8]([CH:34]([CH3:35])[CH3:36])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:4][CH:3]=1)[CH2:42]2
Reactant: O=C(CCl)N1CC2CCC(CC2)C1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CC4CCC(CC4)C3)cc2)C(C)C)c1
Yield: 34.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 1-(3-azabicyclo[3.2.2]non-3-yl)-2-chloroethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.0 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[CH3:12][C:13]1([CH3:23])[NH:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]([NH2:22])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[CH3:12][C:13]1([CH3:23])[N:17]([C:8](=[O:10])[CH2:7][N:5]2[CH2:6][CH:2]([OH:1])[CH2:3][C:4]2=[O:11])[CH2:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: O=C(O)CN1CC(O)CC1=O
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CN1CC(O)CC1=O

Procedure:
To a stirred solution of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid (3.18 g) and 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (3.5 g) in 100 ml of dimethylformamide at room temperature, 4.12 g of DCC were added at once. After 5 hours the solvent was evaporated under vacuum and the residue was suspended in 50 ml of stirred water. After 10 minutes the solid was filtered off and the water evaporated under reduced pressure. The residue was triturated with isopropanol and collected, affording the title product as a white powder m.p. 248°-250° C. (decomp).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([NH:24][C:19]3[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Product: O=C(Nc1ccccc1NC(=O)c1ccc2c(Cl)c[nH]c2c1)OCC1CCN(c2ccncc2)CC1

Procedure:
Using the procedure described in Example 23, Part C, and purifying with preparative RPHPLC method A, N2-[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine (326 mg, 1.0 mmol) and 3-chloroindole-6-carboxylic acid (195 mg, 1.0 mmol) yielded the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2nc3ccc(OCCN4CCCCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 1-(2-chloroethyl)piperidine hydrochloride essentially as previously described. mp 167° C., NMR, IR, MS 570.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25].CC([O-])=O.[Na+]>CCO>[CH2:23]([O:26][N:27]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])[CH:24]=[CH2:25]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Reactant: C=CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCON=C(C)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 79.4 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (168 mg, 0.50 mmol), O-allylhydroxylamine hydrochloride (60 mg, 0.53 mmol) and anhydrous NaOAc (43 mg, 0.53 mmol) in EtOH (3 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:99) to afford N-[2-(1-allyloxyiminoethyl)-5-trifluoromethylphenyl]trifluoromethanesulfonamide 241 (155 mg, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.82, br s, 1H, 7.98, s, 1H, 7.65, d, J=8.2 Hz, 1H; 7.49, d, J=8.2 Hz, 1H; 6.02, m, 1H, 5.44, d, 3J=17.2 Hz, 1H, 5.37, d, 3J=10.4 Hz, 1H, 4.72, d, J=6.0 Hz, 2H, 2.38, s, 3H. HRMS (M+) 390.0465.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:19])[CH:9]([CH:10]=[CH:11][C:12]([O:14]C)=[O:13])[CH:8]1[C:16]([OH:18])=[O:17].[CH3:20][C:21]1(C)[CH:23](C=C(Br)Br)[CH:22]1C([O-])=O.O1CCCC1>C1CCCCC1>[CH3:6][C:7]1([CH3:19])[C@@H:9]([C:10]#[C:11][C:12]([OH:14])=[O:13])[C@H:8]1[C:16]([O:18][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:17]
Reactant: COC(=O)C=CC1C(C(=O)O)C1(C)C
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Temperature: -60 °C
Reaction time: 1 h

Procedure:
60 ml of a 20% solution of butyllithium in cyclohexane were added at -65° C. to a mixture of 26 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate and 175 ml of anhydrous tetrahydrofuran and the mixture was stirred at -60° C. for one hour. A current of carbon dioxide was bubbled through the mixture for 90 minutes and the mixture was poured into an ice-water mixture containing N sodium hydroxide. The alkaline aqueous phase was acidified to a pH of 4 and was extracted with ether. The organic phase was dried and evaporated to dryness under reduced pressure. The residue was crystallized from petroleum ether (b.p.=60°-80° C. to obtain 8.3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(3-hydroxy-3-oxo-1-propynyl)-cyclopropane-1-carboxylate melting at 144° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][NH:5][C:6]=1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:29](N)=[NH:30]>C(O)C>[O:9]=[C:7]1[NH:30][CH:29]=[N:1][C:2]2[C:3]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:4][NH:5][C:6]1=2
Reactant: CCOC(=O)c1[nH]cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1N
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(=O)[nH]cnc23)CC1
Yield: 102.9 %

Procedure:
tert-Butyl 4-[4-amino-5-(ethoxycarbonyl)-1H-pyrrol-3-yl]piperidine-1-carboxylate (466 mg, 1.38 mmol) was dissolved in ethanol (8 mL), and then formamidine acetate (863 mg, 8.29 mmol) was added, followed by heating under reflux for 14 hours. The reaction liquid was cooled, and the precipitated solid was filtered and washed with ethanol to give tert-butyl 4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (452 mg, >1000) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=3)[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2C#N)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NC(=O)c3ccc(F)cc3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 789.1 %

Procedure:
To a solution of 4-(3-Amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.976 g, 3.23 mmol) and NEt3 (0.9 ml, 6.48 mmol) in THF (40 ml) was added 4-fluoro-benzoyl chloride (0.42 ml, 0.355 mmol). The solution was stirred with a magnetic stirrer at room temperature overnight and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (2×30 ml) and brine (30 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[2-cyano-3-(4-fluoro-benzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.189 g, 87%). MS: (M+H)+425.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([CH3:26])[NH:6][C:7](=[O:25])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:24])[C@H:14]([CH3:23])[NH:15]C(OC(C)(C)C)=O)[CH3:2].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[N:5]([CH3:26])[NH:6][C:7](=[O:25])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:24])[C@H:14]([CH3:23])[NH2:15])[CH3:2].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the t-butoxycarbonylalanylprolyl-2-azaalanine ethyl ester obtained above is added 15 ml of methylene chloride. The reaction mixture is cooled to 0° and 15 ml of trifluoroacetic acid added. After stirring for 1 hour at 0° and 1 hour at room temperature, the reaction mixture is concentrated in vacuo to yield alanylprolyl-2-azaalanine ethyl ester as its trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:30][CH2:17][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Into a 1-neck round-bottom flask were added 3-[3-({5-chloro-4-[(3-methoxybenzyl)amino]pyrimidin-2-yl}amino)phenyl]propan-1-ol (0.18 g, 0.45 mmol) and DCM (5 mL). To the reaction mixture was added a solution of boron tribromide in methylene chloride (3.0 mL, 3.0 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when NaHCO3 (saturated aqueous solution, 10 mL) was added. The mixture was allowed to warm up to rt and DCM was added. The aqueous layer was extracted with DCM twice. The organic layers were combined, dried, filtered, and concentrated under vacuum to give the desired product as an off-white powder (150 mg, 74%). LCMS for C20H21BrClN4O (M+H)+: m/z=447.0, 449.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH2:10]1.[CH3:28][NH2:29].O>CN(C)C=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:29][CH3:28]
Reactant: CN
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CC[C@@H]2O
Solvent: O
Solvent: CN(C)C=O
Product: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 2 g of 7α-(5-bromopentyl)-11β-fluoro-estra-1,3,5(10)-triene-3,17β-diol in 20 ml of dimethylformamide is stirred with 8 ml of a 40% aqueous methylamine solution for 3.5 hours at 80° C. Then, it is added to water, extracted three times with ethyl acetate, washed with water and common salt solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.77 g of 11β-fluoro-7α-[5-(methylamino)-pentyl]-estra-1,3,5(10)-triene-3,17β-diol is obtained.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH2:6]1.[OH-].[Na+]>CS(O)(=O)=O>[NH:1]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]1=[O:15]
Reactant: O=C1CC=Cc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCc2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Sodium azide (1.95 g, 30 mmol) was added in small portions to a solution of 3,4-dihydro-[(2H)-naphthalenone (2.92 g, 20 mmol) in CH3SO3H (50 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, 1 hr at room temperature, poured into ice (400 mL), basified until pH>8 with 1N NaOH at 0° C. and extracted with ether (3×100 mL). The combined organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:1) gave 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g, 85%) as a white solid.]H NMR (CDCl3, 300 MHz) δ 2.18–2.32 (m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 7.22 (d, J=7.0 Hz, 2H), 8.10 (br, 1H) ppm.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN(C)[CH:28]=[O:29].C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[OH:29][CH2:28][C:23](=[O:25])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)CO)cc1
Temperature: 95 °C

Procedure:
To a suspension of about 60.0 g of (4-tetradecyloxyphenyl)acetic acid in about 400 ml of methylene chloride containing about 0.63 ml of dimethylformamide was added, over about 10 minutes about 27.31 g of oxalyl chloride. After about 2 hours the solvent was removed, the residue was dissolved in hexane and filtered through celite. The solvent was removed and the residue dried in vacuo. An about 110.82 g portion of tris-trimethylsilyloxyethylene was added and the solution was heated at about 95° C., under argon, for about 5 hours. The solution was poured into a mixture of about 30 ml of concentrated hydrochloric acid (about 12N) about 170 ml of water and about 200 ml of tetrahydrofuran with stirring and heat. This mixture was refluxed about 10 minutes, ethyl acetate was added, the warm organic layer separated and washed with brine, saturated sodium bicarbonate solution, then brine, dried and the solvent removed, giving, after recrystallization from hexane, about 52 g of the desired title compound as a white solid, mp. 84°-85° C.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH3:27])=[O:26]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCCCNC
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCN(C)C(=O)CCCCCCCBr
Reaction time: 0.5 h

Procedure:
9.1 ml of N-methylmorpholine and then 10.4 ml of isobutyl chloroformate were added dropwise at -10° C. to -15° C. to a solution of 5 g of 8-bromo octanoic acid in 200 ml of methylene chloride. The mixture was stirred for 30 minutes at -10° C. to -15° C. and then at this temperature, 13 ml of N-methylbutylamine were added. The mixture was allowed to rise ambient temperature and stood for 40 minutes. Then, 150 ml of a saturated solution of sodium bicarbonate were added and the mixture was stirred for 10 minutes. After decanting, extraction was done with methylene chloride and the extracts were washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride-acetone 95-5) to obtain 6.14 g of the expected product.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C1OCCOCCOCCOCCOCCOC1>[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:1][CH2:2][CH2:3][OH:4])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: OCCS
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CSCCO)cc1
Temperature: 25 °C
Yield: 119.3 %

Procedure:
β-Mercaptoethanol (3.3 mL, 47.2 mmol) was added to a suspension of 4-nitrobenzyl bromide (10.0 g, 46.3 mmol), K2CO3 (16.1 g, 116.5 mmol), KI (154 mg, 0.9 mmol), and 18-crown-6 (258 mg, 1.0 mmol) in acetone (105 mL). The mixture was refluxed under N2 for 1.5 h, cooled to room temperature, filtered through a pad of celite, and concentrated in vacuo. The filtrate was poured into water (100 mL) and extracted with Et2O (2×100 mL). The extracts were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil (11.78 g), which was used in the following step without purification. MS: M(C9H11NO3S)=213.26, (M−OH)+=196.0.