Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:28]3[CH2:29][CH2:30][N:25]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:26][CH2:27]3)=[N:10][C:4]=2[CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1ccccc1O2
Temperature: 25 °C
Yield: 95.6 %

Procedure:
To a stirred solution of 8-chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one (0.3 g; 1.22 mmol) in dry toluene (10 mL) at room temperature was added 1-benzyl piperazine (1.0 mL; 5.61 mmol; Aldrich) followed by the dropwise addition of TiCl4 (1M in toluene, 1.47 mL; 1.47 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution (30%, 50 mL). The resulting mixture was extracted with dichloromethane (4×50 mL), and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using ethyl acetate:hexane (5:1→4:1) as the eluant to give 0.471 g (95%) of the title compound as a yellow solid; m.p. 50°-52° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[C:16]4[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[C:16]4[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3nccc(-c4ccccn4)c3c2)cc1
Agent: Cl
Product: Fc1ccc(-c2n[nH]cc2-c2ccc3nccc(-c4ccccn4)c3c2)cc1
Yield: 52.7 %

Procedure:
63 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-4-(2-pyridyl)quinoline obtained in Example 159 and 0.82 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 162, to give 20 mg of the title compound as a colorless amorphous.
Reaction SMILES: CC(O)([C:4]#[C:5][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])C.[OH-].[K+]>C1(C)C=CC=CC=1>[C:5]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])#[CH:4]
Reactant: Cc1onc(-c2ccccc2)c1C#CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1c(-c2ccccc2)noc1C
Temperature: 110 °C
Reaction time: 1.25 h
Yield: 87.5 %

Procedure:
To a solution of 2-methyl-4-(5-methyl-3-phenyl-isoxazol-4-yl)-but-3-yn-2-ol (3.77 g, 15.6 mmol) in toluene (38 mL) was added potassium hydroxide (350 mg, 6.24 mmol) and the reaction mixture was stirred for 1.25 h at 110° C. before being cooled to ambient temperature and separated between ethyl acetate (500 mL) and aqueous ammonium chloride (1 M, 400 mL). The aqueous layer was extracted with ethyl acetate (500 mL) and the combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 90:10) afforded the title compound (2.50 g, 87%) as a yellow solid. MS: m/e=184.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([NH:13][NH:12][C:10]1[CH2:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)(=[O:23])[CH3:22]
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 1 h

Procedure:
To a solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 30 parts by volume of chloroform is added with stirring 0.47 part by volume of acetic anhydride. The mixture is stirred for 1 hour and washed with a saturated aqueous solution of sodium bicarbonate and then with water. The chloroform layer is dried over sodium sulfate and the solvent is evaporated. Addition of methanol yields 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine as white crystals. Recrystallization from a mixture of chloroform and methanol yields powdery crystals melting at 202° C to 204° C (effervescence).
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[CH2:32][CH:31]5[C:33]([O:35]C)=[O:34])=[CH:26][CH:25]=4)[CH:17]=3)=[C:11]([CH3:37])[CH:10]=2)[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO.O1CCCC1>[O:1]=[S:2]1(=[O:38])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][C:27]([CH:30]5[CH2:32][CH:31]5[C:33]([OH:35])=[O:34])=[CH:28][CH:29]=4)[CH:17]=3)=[C:11]([CH3:37])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OC4CCS(=O)(=O)CC4)cc3C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(COc2ccc(C3CC3C(=O)O)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a mixed solution of methyl 2-[4-({4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′- dimethylbiphenyl-3-yl}methoxy)phenyl]cyclopropanecarboxYlate (0.392 g, 0.733 mmol) in methanol (6 mL) and tetrahydrofuran (12 mL) was added 2 M aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 2 hr. 1 M Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-90:10) and recrystallized from ethyl acetate-hexane to give the title compound (0.129 g, yield 34%) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15](O)[C@@H:16]([C:20]2[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:21]=2)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1.[CH3:37][O:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:44]2[CH:43]=[CH:42][C:41]3[C:46](=[CH:47][CH:48]=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:45]=2)[C@@H:16]([C:20]2[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:21]=2)[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1
Reactant: COc1ccc2ccccc2c1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (5 mL) was added to ethyl N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 1, Step A, 600 mg, 1.436 mmol) and 2-methoxynaphthalene (341 mg, 2.15 mmol). The solution was stirred overnight at RT, then the solvent was evaporated and the residue was purified by PTLC to afford the major diastereomer of the title compound. LC2 2.85 min. [M+H]+ 558.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[OH:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27]([C:29]3[N:37]4[C:32]([CH:33]=[CH:34][CH:35]=[CH:36]4)=[C:31]([O:38][CH3:39])[C:30]=3[CH3:40])=[O:28])[CH:23]=2)[NH:18][C:17]1=[O:41]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27]([C:29]3[N:37]4[C:32]([CH:33]=[CH:34][CH:35]=[CH:36]4)=[C:31]([O:38][CH3:39])[C:30]=3[CH3:40])=[O:28])[CH:23]=2)[NH:18][C:17]1=[O:41])[CH3:7]
Reactant: COc1c(C)c(C(=O)c2ccc3[nH]c(=O)n(O)c(=O)c3c2)n2ccccc12
Reactant: CCOC(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)COn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Reaction time: 18 h
Yield: 48.6 %

Procedure:
0.11 ml (0.99 mmol) of ethyl bromoacetate and then 0.14 ml (0.99 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 0.36 g (0.99 mmol) of 3-hydroxy-6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]quinazoline-2,4(1H,3H)-dione in 12.5 ml of ethanol. The reaction medium is stirred for 18 hours and then 0.14 ml (0.99 mmol) of triethylamine and 0.11 ml (0.99 mmol) of ethyl bromoacetate are added. After stirring for 18 hours at ambient temperature, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol mixture. 217 mg of a yellow powder are obtained.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[C:16]([O:20][CH3:21])(=[O:19])[C:17]#[CH:18].Cl>C1COCC1.O.C(OCC)(=O)C>[CH3:21][O:20][C:16]([C:17]1[NH:7][N:6]=[C:5]([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:18]=1)=[O:19]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C#CC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc([Si](C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.2 %

Procedure:
Place trimethylsilyl-diazomethane (2 M in THF) (25 mL, 50 mmol) in THF (50 mL). Cool the reaction to −78° C. and add lithium diisopropylamide (2 M in THF) (25 mL, 50 mmol) over 30 min. Add methyl propiolate (4.45 mL, 50 mmol) and stir at −78° C. for 2 hours. Warm to room temperature and stir for 18 hours. Add ethyl acetate, water, and 1 N HCl. Separate organic layer and extract aqueous with ethyl acetate (2×25 mL). Combine organic extracts, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-60% EtOAc:hexane to yield 3.59 g (36%) of 5-trimethylsilanyl-2H-pyrazole-3-carboxylic acid methyl ester.
Reaction SMILES: CC1C(C)=C2C(CCC(CCCC(CCCC(CCCC(C)C)C)C)(C)[O:9]2)=C(C)C=1O.N1C=CC=CC=1.[CH3:38][O:39][C:40]1[CH:50]=[CH:49][C:43]([CH:44]=[CH:45][C:46](Cl)=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:50]=[CH:49][C:43]([CH:44]=[CH:45][C:46]([OH:9])=[O:47])=[CH:42][CH:41]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 88 %

Procedure:
4.3 g of dl-α-tocopherol (0.010 mol) and 1.34 g of pyridine (0.017 mol) are placed in 20 ml of CH2Cl2 while gassing with argon in a 100 ml 4-necked sulphonation flask provided with a temperature, a 20 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 0.95 g of 4-methoxycinnamic acid chloride (0.015 mol) in 15 ml of CH2Cl2 is added dropwise within 10 minutes. The reaction mixture is heated to reflux temperature for 3 hours. The solution is washed in succession with 10 ml of water, 10 ml of 5% HCl and 10 ml of 5% NaHCO3. After drying (Na2SO4) the solvent is concentrated on a rotary evaporator. The crude product (6.3 g) is chromatographed (toluene) on 150 g of silica gel (0.040-0.063 mm) under 0.5 bar pressure. There are obtained 5.2 g of yellowish d,l-α-tocopherol ester of p-methoxycinnamic acid (yield 88%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH2:33][CH:34]=O)[C:25]=2[N:36]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:31][CH2:32][CH2:33][CH2:34][NH:1][CH:2]3[CH2:3][C:4](=[O:18])[N:5]([C:7]4[CH:8]=[CH:9][C:10]5[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=5[CH:17]=4)[CH2:6]3)[C:25]=2[N:36]=1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCCCNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
In N,N-dimethylformamide (5 ml) were dissolved 6-(4-Amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 148 mg, 0.60 mmol) and 4-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)butanal (148 mg, 0.60 mmol). Sodium sulfate (1.0 g) was added to this solution and the mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (508 mg, 2.40 mmol) was added to the reaction solution and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane, basified by adding a saturated sodium hydrogen carbonate aqueous solution, and the organic layer was then separated and washed in the order of saturated sodium chloride solution, water (3×) and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 53 mg (18%) of the title compound in the form of a light yellow foamy solid.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[N:5]=1>>[CH3:3][C:4]1[C:9]([Br:1])=[CH:8][NH:7][C:6](=[O:10])[N:5]=1
Reactant: Cc1cc[nH]c(=O)n1
Reactant: BrBr
Product: Cc1nc(=O)[nH]cc1Br
Reaction time: 4 h
Yield: 80 %

Procedure:
Bromine (0.004 mol) was added to an aqueous solution (20 ml) of 4-methylpyrimid-2-one (0.002 mol). The reaction mixture was left at room temperature for 4 h before evaporation. The residue was triturated with acetone and recrystallised from acetic acid; yield 80%, m.p. (Found: C, 22.2; H, 2.3; Br, 59.2. Calc. for C5H5N2OBr. HBr: C, 22.2; H, 2.22; Br, 59.25).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(O)C.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOCC>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(CCl)cc1
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc(CN2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A solution of 29 g of p-fluorobenzyl chloride in 50 g of reagent ethanol was added dropwise to a stirred solution of 34.5 g of piperazine in 150 g of reagent ethanol. A cold water bath was used to maintain the reaction temperature at 20° C. during the addition. The reaction mixture was stirred for an additional 11/2 hours and then added to 2 liters of ether. Precipitated piperazine hydrochloride was filtered off. The filtrate was concentrated to an oil, which was chromatographed on a silica column, the eluant being a mixture of CH2Cl2 /methanol/ammonium hydroxide in the ratio of 45:5:1. After concentration of appropriate fractions, 21.7 g of 1-(4-fluorobenzyl)piperazine were isolated as a colorless liquid (56% of theory).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])[C:5]([OH:19])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:20][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8](=[O:9])[C:6]=2[N:7]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1nc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2nc(Br)ccc2OCN1Cc1ccc(Cl)cc1
Yield: 71.9 %

Procedure:
To a solution of 6-bromo-N-(4-chlorobenzyl)-3-hydroxypicolinamide (200 mg, 0.59 mmol) and Cs2CO3 (516 mg, 2.93 mmol) in DMF (5 mL) was added chloroiodomethane (382 mg, 1.17 mmol) dropwise at 100° C. for 10 minutes. The mixture was concentrated in vacuo and the residue was suspended in water. The mixture was extracted with EtOAc and the organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude 6-bromo-3-(4-chlorobenzyl)-2H-pyrido[2,3-e][1,3]oxazin-4(3H)-one (150 mg, yield: 73%) without further purification. MS (M+H)+: 353/355.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[CH2:21]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:11][C@@H:10]2[C@@:2]3([CH3:1])[CH2:3][CH2:4][C@@H:5]4[C@@H:20]5[C:14](=[CH:15][C:16]([CH2:18][CH2:19]5)=[O:17])[CH2:13][CH2:12][C@H:6]4[C@@H:7]3[CH2:8][CH2:9]2)=[O:37])=[CH:30][CH:29]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CCCCCCOc1ccc(CCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(CCC(=O)O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@@H]5[C@H]4CC[C@]23C)cc1
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a stirred solution of 5.48 g 19-nortestosterone (20 mmol), 5.5 g 3-(4-hexyloxyphenyl)propionic acid (22 mmol), 0.24 g 4-dimethylaminopyridine (DMAP, 2 mmol) and 0.19 g p-toluenesulfonic acid (pTSA, 1 mmol) in 50 ml CH2Cl2 is slowly added at about 15° C. a solution of 5.2 g N,N'-dicyclohexylcarbodiimide (DCC, 25 mmol) in 30 ml CH2CL2. After 4 h at room temperature (no discolouration of the reaction mixture is seen) 1 ml of acetic acid is added to destroy the excess of DCC. Precipitated urea is then filtered off and the filtrate evaporated in vacuo. To the residue 50 ml ethyl acetate is added and, after stirring for 1 h, undissolved urea is filtered off and the filtrate evaporated in vacuo. The residue is crystallized from methanol/water. There is obtained 9.4 g of Anadur® (93% yield) as white crystals having a m.p. of 53°-55° C. and being pure in TLC.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:29](=[O:39])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:40])[CH:27]=3)[N:22]=2)[CH:20]=1)=[O:15])[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:29](=[O:39])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:40][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:27]=3)[N:22]=2)[CH:20]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2nc3ccc(NS(=O)(=O)c4ccccc4)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Benzenesulfonyl chloride (0.131 mL, 1.02 mmol) was added dropwise to a solution of 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.200 g, 0.466 mmol) in pyridine (2.3 mL). The reaction mixture was stirred for 2 h, then quenched with water (15 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (15 mL) and brine (15 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (5-50% EtOAc/hexanes) to yield the titled compound (0.253 mg, 95% yield). MS (ESI/Cl): mass calcd. for C26H31N5O6SSi, 569.2; m/z found, 512.1 [M+H−58]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH2:21][C:20]([C:28]([O:30]C)=[O:29])=[CH:19][C:18]=3[CH:32]=2)=[CH:10][CH:9]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])=[CH:19][C:18]=3[CH:32]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22 g). To the solution was added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23 g) as pale yellow crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:16][CH2:15][CH2:14][C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.[O:41]=[C:42]([CH2:46][CH2:47][CH3:48])[C:43](O)=[O:44]>ClCCl>[O:41]=[C:42]([CH2:46][CH2:47][CH3:48])[C:43]([N:2]1[CH2:16][CH2:15][CH2:14][C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])=[O:44]
Reactant: CCCC(=O)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
8.8 g benzyl prolinate hydrochloride, 9.78 g dicyclohexylcarbodiimide and 6.12 g diisopropylethylamine were reacted together in 50 mL dichloromethane at 0°. 5.51 g 2-oxopentanoic acid in 10 mL dichloromethane was added dropwise at 0°. The pH of the reaction was adjusted to between 8 and 9 with diisopropylethylamine. The reaction mixture was stirred for four hours at 0°, then room temperature overnight. The next day, the reaction mixture was filtered, concentrated to dryness, and partitioned between ethyl acetate and water. The organic layer was washed with 5% sodium bisulfate, 5% sodium bicarbonate, and saturated sodium chloride solutions, and dried with magnesium sulfate. The organic layer was concentrated to give a yellow oil. The oil was then passed through a silica gel column and eluted with ethyl acetate/hexane (4:6) and ethyl acetate/hexane (1:1). Benzyl N-(2-oxopentanoyl)prolinate, [α]D25 -56.9, was isolated.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([O:30]CC)=[O:29])=[N:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:33]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([OH:30])=[O:29])=[N:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Yield: 96.1 %

Procedure:
1.31 g of ethyl 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate was dissolved in 8 ml of ethanol; 8 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by refluxing under heating for 3 hours. After cooling, the ethanol was distilled off; the residue was washed with ethyl acetate; 1 N hydrochloric acid was added to reach pH 5. The precipitated crystal was collected by filtration, washed with water and ethyl acetate, and dried, to yield 1.19 g of the title compound.