Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH2:11].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][CH2:20][O:21][C:22](Cl)=[O:23]>O.C1(C)C(C)=CC=CC=1>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][NH:11][C:22]([O:21][CH2:20][CH2:19][Cl:18])=[O:23]
Reactant: Cc1cccc(C)c1NN
Reactant: O=C(Cl)OCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1NNC(=O)OCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 17.7 g (0.1 mol) 2,6-dimethylphenylhydrazine hydrochloride, 21.2 g (0.2 mol) sodium carbonate in 50 ml water and 50 ml xylene are stirred for 30 minutes at room temperature, then cooled to 5°. 14.3 g (0.1 mol) chloroformic acid 2-chloroethylester is then added over a period of 1 hour, the temperature being maintained at 5°. The mixture is stirred at 5° for another hour, at the end of which 100 ml water are added, the precipitate thus formed filtered off, washed with water and dried. Further work-up as in Example 1b.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=2)[N:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[C:13]([C:9]1[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][C:2]([NH:1][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])=[N:3]2)[CH:12]=[CH:11][CH:10]=1)([OH:15])=[O:14]
Reactant: O=C=Nc1ccccc1
Reactant: NC1=NN(c2cccc(C(=O)O)c2)CC1
Solvent: ClC(Cl)Cl
Product: O=C(NC1=NN(c2cccc(C(=O)O)c2)CC1)Nc1ccccc1

Procedure:
3-Amino-1-(3-carboxyphenyl)-2-pyrazoline (108 mg) and phenylisocyanate (140 mg) in chloroform (10 ml) were heated to reflux overnight. The resultant solid was collected and dried to yield 1-(3-carboxyphenyl)-3-(3-phenylureido)-2-pyrazoline m.p. 255° decomp.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][CH2:36][CH2:37][CH2:38][S:39](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:41])=[O:40]>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][NH:11][S:39]([CH2:38][CH2:37][CH2:36][Cl:35])(=[O:41])=[O:40])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OC(C)(C)C

Procedure:
2-tert-Butoxycarbonylamino-3-octadecylcarbamoyloxypropylamine IV e2 is allowed to react by the same procedure as described in (4). m.p. 112°-115° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[N:17][CH:18]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cncc(F)c1
Product: N#Cc1cc(C=O)ccc1Oc1cncc(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 5-fluoropyridin-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](O)=[O:21])[C:6]2=[O:17].C(N1C=CN=C1)([N:36]1C=CN=C1)=O.[NH4+].[OH-].O>C1COCC1>[C:20]([CH2:19][C@@H:18]([N:5]1[C:6](=[O:17])[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=2[NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:4]1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)(=[O:21])[NH2:36]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc([C@@H](CC(N)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (0.62 g, 1.3 mmol) in THF (5 ml) was added carbonyldiimidazole (0.3 g, 2 mmol) at room temperature. The solution was stirred for 2 hrs at room temperature. To the mixture was added NH4OH (13.8 N, 0.3 ml, 3.9 mmol). The resulting mixture was stirred at room temperature for 4 hrs. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and to the resulting mixture was added ethyl acetate (30 ml). The mixture washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was stirred with ether (5 ml) for 2 hrs and filtered to give (1R)-cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.5 g, 82%): mp 201-203° C.; 1HNMR (CDCl3): δ0.88-0.91 (m, 2H, c-CH2), 1.08-1.11 (m, 2H, c-CH2), 1.45 (t, J=7.5 Hz, 3H, OCH2CH3), 1.65-1.68 (m, 1H, c-CH), 2.98 (dd, J=5, 16 Hz, 1H, CHH), 3.36 (dd, J=5, 16 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.13 (d, J=17 Hz, 1H, NCHH), 4.35 (d, J=17 Hz, 1H, NCHH), 5.42 (broad s, 1H), 5.58-5.64 (m, 1H, CHN), 6.00 (broad s, 1H), 6.83-6.95 (m, 3H, Ar), 7.36 (d, J=9 Hz, 1H Ar), 8.43 (d, J=9 Hz, 1H, Ar), 10.41 (s, 1H); 13C NMR (CDCl3): 8.4, 14.7, 16.1, 38.6, 48.6, 46.7, 53.2, 53.4, 56.0, 64.5, 65.8, 112.2, 119.0, 119.1, 119.5, 121.8, 130.6, 132.8, 136.6, 139.1, 148.7, 149.4, 169.0, 171.8, 172.6; Anal. Calcd. for C24H26ClN3O5: C, 61.08; H, 5.55; N, 8.90; Found: C, 60.89; H, 5.42; N, 8.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[OH:26])=[N:6][CH:7]=1.O[CH:30]1[CH2:39][CH2:38][C:33]2([O:37][CH2:36][CH2:35][O:34]2)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.CCOCC.C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[O:26][CH:30]2[CH2:39][CH2:38][C:33]3([O:37][CH2:36][CH2:35][O:34]3)[CH2:32][CH2:31]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(F)cc1O
Reactant: OC1CCC2(CC1)OCCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NC(=O)c1ccc(F)cc1OC1CCC2(CC1)OCCO2
Yield: 70.3 %

Procedure:
N-(5-Chloropyridin-2-yl)-5-fluoro-2-(4-fluoro-2-hydroxybenzoylamino)-benzamide (1.62 g, 4 mmol), 8-hydroxy-1,4-dioxa-spiro[4.5]decane (630 mg, 4 mmol), and triphenylphosphine (1.04 g, 4 mmol) were dissolved in 4 mL dry DMF, 2 mL dry methylene chloride, and 6 mL dry THF. The resulting slurry was sonicated for 5 min, and then diisopropyl azodicarboxylate (DIAD, 0.8 mL, 4 mmol) was added; and the mixture was sonicated for 2 h. Ether (40 mL) was added, and the mixture was cooled in the freezer overnight. Triphenylphosphine oxide was filtered off, and the resulting solution was concentrated to dryness under reduced pressure. Flash chromatography on silica gel gave the crude product (1.53 g) as a viscous, colorless oil which was used without further purification.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([C:14]([C:20]#[N:21])=[C:15](C#N)[C:16]#[N:17])#[N:13]>CN(C)C=O>[N:7]1([C:1]2[CH:6]=[CH:5][C:4]([C:15]([C:16]#[N:17])=[C:14]([C:20]#[N:21])[C:12]#[N:13])=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: c1ccc(N2CCCC2)cc1
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CN(C)C=O
Product: N#CC(C#N)=C(C#N)c1ccc(N2CCCC2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
4-(pyrrolidino) tricyanovinylbenzene was prepared by mixing 1-phenylpyrrolidine (1.0 g, 6.8 mmol) with tetracyanoethylene (0.9 g, 7 mmol) in 10 mL dimethylformamide at 0° C. The reaction mixture was stirred at room temperature for three hours and at 40° C. for another ten hours. The reaction mixture was quenched with 25 mL water and the dark red colored aqueous solution was extracted with 150 mL methylene chloride and washed several times with water (150 mL). The organic layer was then separated, dried over Na2SO4 and evaporated. The crude products were purified through a silica gel column. The column was eluted with a 1:1 ratio solution of methylene chloride and hexane to yield 1.7 g of the pure product 4 (90% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:1][CH2:2][CH2:6][CH2:7][N:20]1[C:16](=[O:26])[C:17]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:18]2[C:19]1=[O:21]
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3n(CCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 122.1 %

Procedure:
To a suspension of 8.66 g (50 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 100 ml of DMF was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added 14.10 g (50 mmol) of phthalimide, which was stirred for 6 hours at 100° C. After cooling, the reaction mixture was then poured into water, extracted with chloroform. The extract solution was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 11.43 g of the desired compound (61.1%, pale yellow solid).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>C1COCC1>[O:16]=[C:14]([CH3:15])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(CC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1ccc(OCC(=O)O)cc1
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
To a solution of ethyl[4-(2-oxopropyl)phenoxy]acetate (Intermediate 110, 786 mg, 3.33 mmol) in THF (24 mL) water was added (12 mL) and the mixture was stirred for 10 min. Then, lithium hydroxide monohydrate (420 mg, 10.01 mmol) was added and stirring was continued for 3.5 hours at room temperature. THF was evaporated from the reaction mixture and water was added (25 mL). The solution was acidified with 5N HCl until pH 2 was reached and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The resulting organic extract was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the title compound (392 mg, 57% yield).
Reaction SMILES: [C:1]([CH2:3][C@H:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[C:5](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:6])#[N:2].[Li+].[BH4-].Cl>C1COCC1.O>[OH:6][CH2:5][C@@H:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[CH2:3][C:1]#[N:2]
Reactant: N#CC[C@@H](C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccccc1F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC[C@@H](CO)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-[(R)-β-Cyano-α-(2-fluorophenyl)-propionyl]-4-(R)-phenyl-2-oxazolidinone (400 g, 1.18 mol) is suspended in THF (4000 mL) and H2O (25 mL). The reaction mixture is cooled in ice bath to 0° C. and a solution of LiBH4 in THF (2M, 887 ml, 1.77 mol, 1.5 eq) is added slowly. The mixture is then stirred at 0° C. for 2 hours, after which 2N HCl (1500 mL) is cautiously added. The resulting solution is then extracted with Et2O (2×1500 mL). The combined organic phases are then washed with saturated NaCl solution (2×1500 mL), dried over MgSO4 and concentrated in vacuo. The solid 4(R)-phenyl-2-oxazolidinone is recovered by filtration and washed with Et2O (2×100 mL). The filtrate is then chromatographed (silica gel, EtOAc/Hexanes, 1:3) to give β(R)-(hydroxymethyl)-β-(2-fluorophenyl)-propionitrile as an oil.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[Cl:25][C:26]1[C:27]([O:36][CH2:37][C:38]23[CH2:48][C:42]4([F:49])[CH2:43][C:44]([F:47])([CH2:46][C:40]([F:50])([CH2:41]4)[CH2:39]2)[CH2:45]3)=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31](O)=[O:32].COC[CH2:54][S:55]([NH2:58])(=[O:57])=[O:56].CS(N)(=O)=O>>[Cl:25][C:26]1[C:27]([O:36][CH2:37][C:38]23[CH2:48][C:42]4([F:49])[CH2:43][C:44]([F:47])([CH2:46][C:40]([F:50])([CH2:41]4)[CH2:39]2)[CH2:45]3)=[CH:28][C:29]([F:35])=[C:30]([CH:34]=1)[C:31]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:32]
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 150 step 5 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide, the title compound was obtained as a colorless solid (0.035 g, 28%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.20 (d, J=12.28 Hz, 1H), 4.00 (s, 2H), 3.22 (s, 3H), 2.26-2.15 (m, 3H), 2.07-1.97 (m, 3H), 1.82-1.74 (m, 6H); MS (ES−) m/z 468.21, 470.20 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46](=[O:59])[N:47]([S:55]([CH3:58])(=[O:57])=[O:56])[C:48]1[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=1)([CH3:44])([CH3:43])[CH3:42].BrC1C=CC(NS(C)(=O)=O)=CC=1.C(=O)(OC(C)(C)C)OC(C)(C)C.COC(=O)C1C=CC(Br)=CC=1>C(#N)C.CN(C1C=CN=CC=1)C>[C:41]([O:45][C:46](=[O:59])[N:47]([S:55]([CH3:58])(=[O:57])=[O:56])[C:48]1[CH:49]=[CH:50][C:51]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[CH:52][CH:53]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Br)cc1)S(C)(=O)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)c1ccc(Br)cc1
Solvent: CC#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (81 mg) and mesyl-(4-bromo-phenyl)-carbamic acid tert-butyl ester (prepared from N-(4-bromo-phenyl)-methane sulfonamide and di-t butyl carbonate in acetonitrile in the presence of DMAP, 105 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of mesyl-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic acid tert-butyl ester was obtained, and then the PMB groups were removed according to Deprotection method 1, to obtain the desired compound (D-44) as a pale yellow powder (12 mg, 10%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@@H:26]4[CH3:35])=[CH:21][N:20]=3)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=2)=[CH:10][C:9]([F:38])=[CH:8][C:7]=1[N:39]1[CH2:52][CH2:51][N:42]2[C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[C:49]([F:50])=[C:41]2[C:40]1=[O:53])(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[F:50][C:49]1[C:48]2[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=2[N:42]2[CH2:51][CH2:52][N:39]([C:7]3[CH:8]=[C:9]([F:38])[CH:10]=[C:11]([C:12]4[CH:17]=[C:16]([NH:18][C:19]5[CH:24]=[CH:23][C:22]([N:25]6[CH2:30][CH2:29][N:28]([CH:31]7[CH2:32][O:33][CH2:34]7)[CH2:27][C@@H:26]6[CH3:35])=[CH:21][N:20]=5)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=4)[C:6]=3[CH2:5][OH:4])[C:40](=[O:53])[C:41]=12
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 119d (90 mg, 1.0 eq., 0.12 mmol), lithium hydroxide (9.0 mg, 3.0 eq., 0.37 mmol), i-propanol (3 mL), THF (3 mL), and water (2 mL). The mixture was stirred at room temperature for 1 h. It was then filtered and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 119 (42 mg, 49%). MS: [M+H]+ 686.3. 1H NMR (500 MHz, CDCl3) δ 8.54 (dd, J=2.0 Hz, 9.0, 1H), 7.94-7.93 (m, 1H), 7.81 (d, J=4.0 Hz, 1H), 7.45-7.44 (m, 1H), 7.31 (dd, J=3.0, 9.0 Hz, 1H), 7.15-7.14 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 4.71-4.61 (m, 4H), 4.53 (d, J=9.5 Hz, 1H), 4.32-4.31 (m, 2H), 4.15-4.08 (m, 3H), 3.89-3.86 (m, 1H), 3.69 (s, 3H), 3.55-3.43 (m, 2H), 3.07 (m, 2H), 2.57-2.46 (m, 7H), 2.20-2.16 (m, 1H), 1.88-1.76 (m, 4H), 0.98-096 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[C:28]([O:37][CH2:38][CH3:39])(=[O:36])[C:29]1[C:30](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH2:31]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:8]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[C:28]([O:37][CH2:38][CH3:39])=[O:36])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
Triethylamine (1.86 ml) and octadecanoyl chloride (3.67 g) were added to a solution of ethyl anthranilate (2.00 g) in methylene chloride (20 ml). After being stirred for 30 minutes at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding 5.45 g of the aimed compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[Cl:11].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:52]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55]>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[Cl:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=1[CH:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:52]([O:60][CH2:61][CH3:62])=[O:59]
Reactant: COc1cc(Cl)c(Br)cc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1cc(Cl)c(OC)cc1Cl
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.6 %

Procedure:
A solution of 1-bromo-2,5-dichloro-4-methoxybenzene (Intermediate 4-6; 3.82 g, 14.93 mmol), cesium carbonate (14.59 g, 44.78 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.427 g, 0.90 mmol) in toluene (220 mL) was thoughroughly degassed. The mixture was treated with diacetoxypalladium (0.101 g, 0.45 mmol) and diethyl malonate (2.505 mL, 16.42 mmol) and the resulting solution stirred under a nitrogen atmosphere at 100° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature, evaporated to dryness and partitioned between EtOAc (150 mL) and water (100 mL). The mixture was filtered and the aqueous layer was separated and re extracted with EtOAc (150 mL). The organic extracts were combined, dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford diethyl 2-(2,5-dichloro-4-methoxyphenyl)malonate (1.880 g, 37.6%) as a yellow oil.
Reaction SMILES: O[C@@]1(C)C=C[C@H]2[C@H]3[C@H]([C@@H]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=5)=[CH:22][CH:21]=4)C[C@]12C)[C@@H]1C(=CC(=O)CC1)CC3.Cl.CCCCCC.C(OCC)(=O)C>CC(C)=O>[C:26]1([C:23]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=2)[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=1
Reactant: C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](c3ccc(-c4ccc(C#N)cc4)cc3)C[C@@]21C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(-c2ccccc2)cc1

Procedure:
260 mg of 4'-[3,3-[1,2-ethanediylbis(oxy)]-17β-methoxy-17α-methyloestra-5,15-dien-11β-yl][1,1'-biphenyl]-4-carbonitrile are reacted with 0.7 ml of 4 normal aqueous hydrochloric acid in 14 ml of acetone in the manner described in Example 1 r). Column chromatography on silica gel with a mixture of hexane/ethyl acetate yields 218 mg of 4'-17β-methoxy-17α-methyl-3-oxo-oestra-4,15-dien-11β-yl][1,1'-biphenyl]-4-carbonitrile in the form of a white foam.
Reaction SMILES: [C:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[ClH:26].O1CCOCC1>>[ClH:26].[N:13]1([CH2:12][CH:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[C:11]=3[O:10][CH2:9]2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2COc3c(C#N)cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc2c1OCC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound tert-butyl 4-[(7-cyano-2,3-dihydro-1-benzofuran-3-yl)methyl]piperazine-1-carboxylate (76 mg, 0.22 mmol) was added HCl/dioxane (4 N) and the resulting mixture was stirred at room temperature for 3 hours, and then the solvents were removed under vacuum to give the crude 3-(piperazin-1-ylmethyl)-2,3-dihydro-1-benzofuran-7-carbonitrile hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[C:16](Cl)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1cnn2c(-c3ccccc3)nc3ccccc3c12
Yield: 43.1 %

Procedure:
20.4 g (0.1 mole) of 5-(o-aminophenyl)-4-nitropyrazole are dissolved in 200 ml of pyridine. To the solution obtained, 14.0 g (0.1 mole) of benzoyl chloride are added, drop by drop, and the temperature of the reaction mixture is increased by 10° to 15° C., spontaneously. The mixture is reacted for 2 hours, then poured into water, and the product that solidifies is filtered off and recrystallized from dichloroethane. Thus, 12.5 g (43%) of 1-nitro-5-phenylpyrazolo[1,5-c]quinazoline are obtained. M.p.: 187°-188° C.