Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([F:12])[F:11]
Reactant: CC(=O)c1cnc(OCC(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)F)c(Cl)c1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (3.56 g, a white solid) from 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (2.88 g, 12.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:14])[CH:12]=[CH2:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]2[O:10][CH2:13][CH:12]([C:11]#[N:14])[CH:5]([OH:6])[C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CC1COc2ccc(Cl)cc2C1O
Reaction time: 8 h

Procedure:
To a stirred, refluxing mixture of 50 g of 3-chloro-6-hydroxybenzaldehyde and 62 ml of acrylonitrile in 50 ml of water was added dropwise over a three-hour period a solution of 12.8 g of sodium hydroxide in 120 ml of water. Then an additional 62 ml of acrylonitrile was added and the stirred mixture was refluxed for 2 hours, then allowed to stand at room temperature overnight. The crystals which formed were filtered off, washed with water and dried to give a solid, which was recrystallized from ethanol to give 6-chloro-3,4-dihydro-4-hydroxy-(2H)-1-benzopyran-3-carbonitrile (6A), a solid. A mixture of 6A with 250 ml of methanol containing 2 ml of sulfuric acid was refluxed for 4 days and stripped of solvent. The resulting residue was dry column chromatographed over silica gel, using Solvent No. 3 as eluent. The product obtained on workup was rechromatographed and recrystallized from ether to give methyl 6-chloro-2H-1-benzopyran-3-carboxylate (6B), as light yellow needles, mp: 106°-109° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:21])([F:19])[F:20]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: COCCOCCBr
Product: COCCOCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 74 from 1-bromo-2-(2-methoxyethoxy)ethane and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=449.0 (MH+).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1.[CH2:51]1[CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60](O)=[O:61])[S:54][S:53][CH2:52]1>O1CCCC1>[S:53]1[CH2:52][CH2:51][CH:55]([CH2:56][CH2:57][CH2:58][CH2:59][C:60]([NH:50][CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][O:42][CH2:43][CH2:44]2)=[O:61])[S:54]1
Reactant: O=C(O)CCCCC1CCSS1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCCCC1CCSS1)NCCN1CCOCC1
Reaction time: 20 h
Yield: 88 %

Procedure:
4.5 g of hydroxybenzotriazole, 10.5 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 7.8 g of diisopropylethylamine and 3.9 g of 2-morpholino-1-ethylamine are added at room temperature to a solution of 6.2 g of thioctic acid in 180 ml of tetrahydrofuran. After 20 hours, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed and then dried over Na2SO4. Concentration under reduced pressure yields 8.4 g of the expected product.
Reaction SMILES: O=C1NC2C=CC=CC=2S[C@H](C2C=CC=CC=2)[C@@H]1NC(=O)[C@H](C)NC(=O)CC1C=CC=CC=1.Br.[NH2:35][C@H:36]1[C:42](=[O:43])[NH:41][C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[S:38][C@H:37]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:71](O)=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1>>[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:71]([NH:35][C@@H:36]2[C:42](=[O:43])[NH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[S:38][C@@H:37]2[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1
Reactant: CSCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Agent: Br
Agent: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: CSCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that (2,3-cis)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (105 mg) was used as the amine component and N-[(3,5-difluorophenyl)acetyl]-L-methionine (109b) (91 mg) was used as the acid component to afford the title compound as a 1:1 mixture with the (2S,3S) diastereomer (63 mg), white solid, m.p. 85-90° C. 1H NMR (300 MHz, d6-DMSO) δ 1.55 (m, 4H), 2.20 (s, 3H), 2.40 (m, 12H), 3.03 (m, 4H), 4.26 (m, 1H), 4.72 (m, 1H), 5.17 (d, 1H, J=7 Hz), 5.829 (d, 1H, j=6 Hz), 6.89-7.79 (m, 12H), 8.21 (m, 1H), 10.53 (m, 1H). MS APCI, m/z=556(M+1). LC/MS: 2.55 min.
Reaction SMILES: [Cl:1][C:2]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]([F:17])[C:2]=2[Cl:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: Nc1ncccc1OCc1c(Cl)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A stirring solution of 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrile was cooled to 0° C. using an ice bath. To this solution was added N-bromosuccinimide (NBS) (5.33 g, 0.03 mol) portionwise. The reaction was stirred at 0° C. for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 mL), and purified via silica gel chromatography. The solvents were then removed in vacuo to yield 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (5.8 g, 0.015 mol, 51%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ1.85-1.95 (d, 3H), 4.7-5.0 (brs, 2H), 5.9-6.01 (q, 1H), 6.8-6.95 (d, 1H), 7.01-7.2 (t, 1H), 7.4-7.45 (m, 1H), 7.8-7.85 (d, 1H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:27][NH:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30].N1C=CC=CC=1C1C=CC=CN=1>[Cu-]=O.CN(C=O)C>[CH2:32]([S:29]([N:28]([CH3:27])[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)(=[O:31])=[O:30])[CH3:33]
Reactant: CCS(=O)(=O)NC
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: O=[Cu-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)c1nc(C(=O)OC)c(OS(=O)(=O)c2ccc(C)cc2)c2ncccc12
Temperature: 118 °C
Reaction time: 2 h

Procedure:
In a dried sealable pressure tube flushed with argon was placed methyl 5-bromo-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (2.0 g, 4.57 mmol), prepared as described in Example 2, Step 2), N-methylethanesulfonamide (1.13 g, 9.15 mmol), dry DMF (4 mL) and copper(I) oxide (785 mg, 5.49 mmol) and 2,2′ bipyridyl (857 mg, 5.49 mmol). The tube was capped and heated to 118° C. for 2 hours. The reaction was cooled and filtered through a glass fiber filter, washing with chloroform. The filtrate was diluted with chloroform (about 100 mL total volume) and stirred with an EDTA solution (5 g EDTA in 100 mL water) for two hours or until the aqueous layer became aqua in color and the organic layer became yellow. The layers were separated and the aqueous layer was extracted twice more with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was redissolved in 2 mL of DMSO and purified by preparative HPLC (Gilson semi preparative HPLC system using a Waters Nova pak column (10×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.025% TfEA)/acetonitrile (0.025% TFA) at 35 mLjmin) and the desired fractions were freeze dried to give the product as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=[O:9])=[C:4]([NH:11][C:12]([C:14]([O:16]CC)=O)=[O:13])[CH:3]=1.C(O)C>CN(C)C=O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([OH:9])[C:14](=[O:16])[C:12](=[O:13])[NH:11]2
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2n(O)c1=O
Yield: 33.4 %

Procedure:
A solution of 0.5 g (1.83 mmol) 1-chloro-3-ethoxalylamino-4-nitrobenzene in 15 ml dimethylformamide was hydrogenated at atm. pressure by using 0.5 g Ra-Ni as a catalyst. The residue was stirred with ethanol to give 0.13 g (30%) of 6-chloro-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 11.8 (1H, broad s), 7.17 (3H, m). MS (m/e): 212 (M30 , 60%).
Reaction SMILES: C([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([NH2:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:57]>C(O)(=O)C.O1CCOCC1>[ClH:57].[NH2:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([NH2:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(N)=O)C3
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(N)=O)C3
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.0 g of Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxamide in 5.0 ml of glacial acetic acid is added 5.0 ml of a 6 N solution of hydrogen chloride in dioxane. The reaction mixture is stirred for 20 minutes at room temperature. The solvent is removed under reduced pressure, and the residue is dissolved in 125 ml of water. The solution is lyophilized to give L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxamide hydrochloride which is represented by the following formula ##STR29##
Reaction SMILES: [NH3:1].[N+:2]([NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9])([O-:4])=[O:3].C(Cl)Cl>CO>[N+:2]([NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9])([O-:4])=[O:3].[NH4+:1]
Reactant: N
Agent: CCOC(=O)N[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: [NH4+]

Procedure:
Anhydrous NH3 (g) was bubbled into a stirred solution of ethyl N-nitrocarbamate (503.0 g, 3.75 mol, mp 63°-66° C.), CH2Cl2 (1625 mL) and dry CH3OH (825 mL), precooled to 9° C. under N2, until the exothermic reaction subsided (the NH3 addition rate was controlled so as not to exceed a reaction temperature of 23° C.). After the NH3 addition was complete, the mixture was filtered and the collected solid was dried under high vacuum (overnight) to give ammonium ethyl N-nitrocarbamate as colorless crystals (563.0 g, 99%). mp 175°-176° C. IR (KBr) 3230 (s), 3000 (m), 1725 (s) and 1685 (s), 1445 and 1395 (s), 1310 (m), 1220 (s), 1100 (S), 1030 (m) cm-1. 1H NMR (90 MHz, d6 -DMSO) δ 7.30 (bs, 4H, exch D2O), 3.90 (q, 2H, J=4.5 Hz), 1.10 (t, 3H, J=4.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][CH2:15]/[CH:16]=[CH:17]/[CH:18]=O)[CH2:7][CH2:6]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28][CH:29]=[CH:30][C:31](=[O:33])[CH3:32]>>[C:31]([C:30]1[CH:16]([CH2:15][CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:17]=[CH:18][N:28]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[CH:29]=1)(=[O:33])[CH3:32]
Reactant: COc1ccc2c(c1)CCC(CC/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1ccccc1Cl
Product: COc1ccc2c(c1)CCC(CCC1C=CN(Cc3ccccc3Cl)C=C1C(C)=O)C2=O

Procedure:
The title compound 73 is prepared according to the procedure reported in step D of Example 8 with aldehyde 76 (121 mg, 0.47 mmol) and enamine 45 (138 mg, 0.56 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 74 as a yellow oil. (Yield 67.5 mg, 32%).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[F:28][C:29]([C:34]([F:55])([F:54])[C:35]([F:53])([F:52])[C:36]([F:51])([F:50])[C:37]([F:49])([F:48])[C:38]([F:47])([F:46])[C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])=[CH:30][CH2:31][NH:32][CH3:33]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:32]([CH2:31][CH:30]=[C:29]([F:28])[C:34]([F:54])([F:55])[C:35]([F:52])([F:53])[C:36]([F:50])([F:51])[C:37]([F:48])([F:49])[C:38]([F:46])([F:47])[C:39]([F:44])([F:45])[C:40]([F:43])([F:42])[F:41])[CH3:33]
Reactant: CNCC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Solvent: CN1CCCC1=O
Product: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one and 1.83 g of (3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amine are dissolved in 20 ml of N-methylpyrrolidone and stirred for 1 hour at a bath temperature of 80° C. After the reaction solution is cooled to room temperature, the batch is added to saturated common salt solution, extracted with diethyl ether, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with ethyl acetate as an eluant, 1.2 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amino]-pentyl}-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([NH:28][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][NH:12]3)=[CH:8][CH:7]=2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3cn[nH]c3c2)cc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3cn[nH]c3c2)cc1NCc1ccccc1
Temperature: 100 °C

Procedure:
A stirred solution of the nitro compound (2 mmol) in DMF (4 mL) was added with benzylamine (4 mmol) and contents were heated at 100° C. for 6 h. The reaction mixture was cooled to RT and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo. The residue obtained was purified on silica gel column chromatography using hexane/EtOAC as eluent to provide the product, benzyl-[5-(1H-indazol-6-yloxy)-2-nitrophenyl]-amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
0.18 g (0.04 equivalent) of Pd(PPh3)4 and then 1.2 g (0.0084 mol) of 5-chloro-2-thiopheneboronic acid are added to a solution of 1.4 g (0.0038 mol) of ethyl 2-[(4-bromophenyl)oxy]-4-cyclohex-1-en-1-ylbutanoate in 20 ml of dimethoxyethane. 4.2 ml of 2M sodium carbonate solution are added at room temperature. The reaction mixture is stirred overnight and then refluxed for 2 hours. After cooling to room temperature, the mixture is taken up in water and extracted with ethyl acetate. The extract is washed with 1N sodium hydroxide and then with saturated aqueous NaCl solution and finally dried over Na2SO4. After concentrating, the black oil obtained is purified by flash chromatography (95/5 heptane/ethyl acetate). 1.1 g of a thick oil are obtained.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C@H:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[CH:43][N:42]=[N:41]5)[O:36][C:35]4=[O:45])=[CH:30][C:29]=3[F:46])=[CH:24][N:23]=2)[CH2:18]1)=[O:14])=O)(C)(C)C.C(O)(=O)C.Cl>CO>[CH3:6][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C@H:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[CH:43][N:42]=[N:41]5)[O:36][C:35]4=[O:45])=[CH:30][C:29]=3[F:46])=[CH:24][N:23]=2)[CH2:18]1)=[O:14]
Reactant: CN(CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CNCCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl 5-[(tert-butoxycarbonyl)(methyl)amino]pentanoate (Example 34: 0.5 g, 0.77 mmol) was combined with acetic acid (15 ml) and hydrochloric acid (4M solution in dioxane, 1 ml, 4 mmol). The suspension was warmed for 2 minutes at approximately 80° C. to dissolve most of the suspended material. The mixture was stirred at room temperature for an additional 15 minutes then concentrated under reduced pressure. The residual solids were dissolved in water (40 ml) then extracted twice with ethyl acetate (20 ml). Evaporation of the aqueous layer followed by drying under reduced pressure gave a solid that was dissolved in methanol (1 ml) and precipitated by the addition of diethyl ether (10 ml). The solution was decanted off and the precipitation was repeated. The resulting sticky oil was dried in vacuo at 50° C. to give the hydrochloride salt of the title compound as a hygroscopic solid (0.46 g), melting point: 184° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](/[C:8](=[CH:14]/[N:15](C)C)/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.Cl.[O:24]1[CH2:30][CH:29]([NH:31]N)[CH2:28][O:27][CH2:26][CH2:25]1>C(#N)C.O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[N:31]([CH:29]3[CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:30]3)[N:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: NNC1COCCOC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of (Z)-ethyl 2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)acrylate (642 mg) in acetonitrile (8 mL) was added a solution of (1,4-dioxepan-6-yl)hydrazine hydrochloride (341 mg) obtained in Preparation Example 16 in water (2 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and further stirred at 50° C. for 9.5 hours. The reaction mixture was returned to room temperature and partitioned by adding ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were sequentially washed with the saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/heptane, 20 to 33%) to give the title compound (408 mg).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][C:21]([CH3:25])=[N:20]2)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>O>[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH:22]=[C:21]([CH3:25])[N:20]2[CH3:1])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=NN(c2cccc(Cl)c2)C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)n1C
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 52.7 %

Procedure:
90 g of p-toluenesulfonic acid was added to 50 g of 1-(3-chlorophenyl)-3-methyl-2-pyrazolin-5-one [Chemical Abstracts Registry Number (90-31-3)], and the resulting mixture was stirred on an oil bath at 150° C., for 2.5 hours. The reaction mixture was allowed to cool down to 100° C. or less. A solution prepared from 25 g of sodium hydroxide and 150 ml of water was added dropwise thereto. After adding thereto 350 ml of water, the mixture was extracted with chloroform. The chloroform phase was separated and then dried over anhydrous potassium carbonate. After insoluble materials were filtered off, the filtrate was concentrated to dryness to obtain 28.1 g of 1-(3-chlorophenyl)-2,3-dimethyl-3-pyrazolin-5-one. When recrystallization was carried out from ethyl acetate, crystals having a melting point of 98° to 100° C. were obtained.