Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42]>CS(C)=O.O>[NH2:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH:42][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1cccc(N)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(N)c4)n3Cc3ccccc32)cc1C
Yield: 57.2 %

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (0.125 g; 0.275 mmol), and 3-aminobenzylamine (0.071 g; 0.577 mmol), in dimethylsulfoxide (5 mL) was stirred at 80° C. for 18 hours. The solution was diluted with water and extracted into dichloromethane. The extracts were dried over anhydrous sodium sulfate and evaporated to yield the title compound as an amorphous white solid (0.085 g; 57%), m.p. 105-115° C. MS [(+)ESI, m/z]: 541.2 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CCN(C(C)C)C(C)C.O>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:7]=1
Reactant: Clc1cc(COC2CCCCO2)ccn1
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: c1cc(COC2CCCCO2)cc(N2CCNCC2)n1
Yield: 80.2 %

Procedure:
A solution of 2-chloro-4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine (8.7 g, 38.2 mmol) and piperazine (16.4 g, 191 mmol) in DIEA (30 mL) was heated at 150° C. for 48 h. The reaction mixture was diluted with H2O (1000 mL), and the solution was extracted with DCM/MeOH (10/1, 3×400 mL). The combined organic layers were washed with H2O (100 mL), and brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=15:1) to afford 1-(4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl) piperazine as yellow oil (8.5 g, 80%). MS (ES+) C15H23N3O2 requires: 277, found: 278[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[CH:18]=O)[CH:9]=2)[N:3]=1.[CH3:20][NH:21][C:22]1[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.CC(O)=O.C([O-])(O)=O.[Na+]>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[N:21]([CH3:20])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:28]=3)[CH:9]=2)[N:3]=1
Reactant: CNc1ccccc1N
Reactant: Cc1cc(-n2nc(C)nc2C)cc([C@@H]2C[C@H]2C=O)n1
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(-n2nc(C)nc2C)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-2-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-2-yl)cyclopropanecarbaldehyde (24-7, 74 mg, 0.289 mmol), N1-methylbenzene-1,2-diamine (35 mg, 0.289 mmol), copper(II) sulfate (51 mg, 0.318 mmol), and AcOH (35 mg, 0.578 mmol) in ethanol (3 mL) was stirred at room temperature overnight. NaHCO3 (100 mg) was added and the mixture was stirred for 5 minutes and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (10% methanol in DCM) and reverse phase chromatography (10-100% acetonitrile in water) to afford trans-2-(2-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-2-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (24-8) as a light yellow oil. 1H NMR (300 MHz, CDCl3) 57.73-7.65 (m, 1H), 7.33-7.18 (m, 4H), 7.14 (d, 1H, J=1.7 Hz), 3.83 (s, 3H), 2.88-2.75 (m, 2H), 2.60 (s, 3H), 2.59 (s, 3H), 2.41 (s, 3H), 1.98-1.87 (m, 2H). LRMS m/z (M+H) 359 found, 359 required.
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].CI.[C:7]([NH:14][C@@H:15]([C:17]([OH:19])=[O:18])[CH3:16])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[H-].[Na+]>C1COCC1>[CH3:12][C:10]([CH3:13])([O:9][C:7]([N:14]([CH2:3][CH:2]=[CH2:1])[C@@H:15]([C:17]([OH:19])=[O:18])[CH3:16])=[O:8])[CH3:11]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C=CCN(C(=O)OC(C)(C)C)[C@H](C)C(=O)O
Yield: 99 %

Procedure:
Allyl iodide (6.72 g, 40.0 mmol) replaced methyl iodide and Boc-(D)-alanine (1.89 g, 10.0 mmol) replaced Z-(D)alanine in the reaction of Example 15. They were reacted using sodium hydride (30.0 mmol, 50% suspension in mineral oil) and THF (30 ml). 2.27 g of oil was obtained using the procedure and work-up of Example 15.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.CN(C)CCN(C)C.C([Li])CCC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.ClCC1ON=CC=1.[F:51][C:52]1[CH:53]=[C:54]([OH:66])[CH:55]=[C:56]([C:58]2([O:64][CH3:65])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[CH:57]=1>O1CCCC1.O1CCOCC1.[OH-].[Na+].O>[F:51][C:52]1[CH:53]=[C:54]([CH:55]=[C:56]([C:58]2([O:64][CH3:65])[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)[CH:57]=1)[O:66][CH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: CN(C)CCN(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: ClCc1ccno1
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: COC1(c2cc(F)cc(OCc3onc(-c4ccccc4)c3-c3ccc(S(N)(=O)=O)cc3)c2)CCOCC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
A solution of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (1.0 g, 3.2 mmol) and N,N, N′, N′-tetramethylethylenediamine (1.12 g, 9.6 mmol) in tetrahydrofuran (100 mL) was cooled to −78° C. Butyllithium (6 mL, 1.6 M, 9.6 mmol) was then added to this solution. After 30 min, hexachloroethane (2.27 g, 9.6 mmol) was added to the reaction mixture, the reaction mixture was warmed to −30° C., and then quenched with dilute hydrochloric acid. The reaction mixture was extracted with ethyl acetate (100 mL), washed with brine, dried and concentrated to afford a 1:1 mixture of the desired 5-chloromethyl isoxazole product and the starting material as an inseparable mixture, which was carried to the next stage without further purification. The crude 5-chloromethyl isoxazole (0.25 g, 0.718 mmol) was added to a solution of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (0.324 g) in dioxane (5 mL) and aqueous sodium hydroxide (1N, 2.86 mL), and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water and brine, dried, filtered, and concentrated. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:2 ethyl acetate in hexane, to give 0.130 g (67%) of 4-[5-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)-phenoxy]-methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide as a crystalline solid: 1H NMR (CDCl3/300 MHz) δ 7.93 (d, 2H, J=8.5 Hz), 7.42-7.36 (m, 7H), 6.78-6.54 (m, 3H), 5.15 (s, 2H), 379-3.82 (m, 4H), 2.99 (s, 3H), 1.88-1.86 (m, 4H). FABMS m/z =545 (M+Li). HRMS calcd for C28H27N2FO6S 538.1652. Found 539.1652 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.S(Cl)(C)(=O)=O.CNC>ClC(Cl)C.CO.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:13]([CH3:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)nc1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CO
Product: CN(C)CCc1ccc(Br)nc1
Temperature: 4 °C
Yield: 26.2 %

Procedure:
2-(6-Bromopyridin-3-yl)ethanol (40 mg, 0.20 mmol) was dissolved in dichloroethane (3 ml), 200 mg of triethylamine was added to the solution, and the mixture was stirred at 4° C. under ice cooling. Mesyl chloride (68 mg, 0.60 mmol) was added to the reaction solution. After the dropwise addition, the mixture was stirred at 4° C. for 1 hr under ice cooling and was further stirred at room temperature for 30 min. The reaction solution was poured into 10 ml of iced water, was extracted with ml of ethyl acetate, and the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure. The residue was dissolved in DMF (2 ml), and the solution was stirred at room temperature. A 2 M solution (1 ml) of dimethylamine (2 mmol) in methanol was added thereto, and the mixture was stirred at 5.0° C. for 4 hr. The reaction solution was poured into 10 ml of iced water and was extracted with 20 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1) to give 12 mg (yield 28.1%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CCCCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCCCC1
Temperature: 140 °C
Yield: 32.6 %

Procedure:
2,6-Dichloro-3-nitropyridine (5 g, 25.9 mmol) and cyclohexanamine (5.14 g, 51.8 mmol) were added to ethanol (17.5 mL). The reaction mixture was heated at 140° C. by microwave irradiation for 3 h. A yellow solid precipitated out. The solid was filtered, washed with cold ethanol, and dried under vacuum to afford the title compound (2.162 g) without further purification. LCMS m/z=256.40 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:33])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:28]5[O:29][CH2:30][O:31][C:27]=5[C:26]([C:32]([NH:34][CH:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[O:33])=[CH:25][CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1CCC(NC(=O)c2ccc(N)c3c2OCO3)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c3c2OCO3)CC1
Temperature: 160 °C

Procedure:
To 2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 108 mg, 0.35 mmol) and 7-amino-N-(1-methylpiperidin-4-yl)benzo[d][1,3]dioxole-4-carboxamide (Intermediate 223; 98 mg, 0.35 mmol) in 4-methyl-2-pentanol (3 mL) was added p-toluenesulphonic acid monohydrate (139 mg, 0.73 mmol) and the reaction mixture heated at 160° C. by microwave irradiation for 1 hour.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.N1(C(N)=O)CCOCC1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[CH:26]=[N:27][CH:28]=1.S(=O)(=O)(O)O>C1COCC1>[Br:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([CH:24]=1)[CH:29]=[O:30]
Reactant: O=C(O)c1cncc(Br)c1
Agent: NC(=O)N1CCOCC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cncc(Br)c1
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
1.75 g of lithium aluminium hydride powder are suspended in 64 g of THF. A mixture of 5.9 g of ethyl acetate and 28 g of THF is subsequently added dropwise with cooling. After 30 minutes, this reaction mixture is added dropwise at 0° C. to 10° C. to a solution of 5.0 g of 5-bromopyridine-3-carboxylic acid morpholinamide from Example 3(a) in 30 g of THF (this corresponds to 150% excess of the reducing agent). After 1 hour, the reaction mixture is poured into 35 ml of 12% sulfuric acid, and the organic phase is evaporated to dryness. Recrystallisation from MTB ether and drying gives 1.91 g of product (=55.7% of theory). Melting point 95° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].[CH:12]1(OBr)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>>[CH:12]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH2:5][OH:6])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrOC1CCCC1
Reactant: COc1ccc(CO)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: COc1ccc(CO)cc1OC1CCCC1
Yield: 35.8 %

Procedure:
From 3-hydroxy-4-methoxybenzyl alcohol (50 g, 0.324 mol), cyclopentyloxybromide (70 ml, 0.648 mol), caesium carbonate (72.83 g, 0.222 mol) and sodium iodide (5.63 g, 0.037 mol). Chromatography (SiO2 ; EtOAc-C6H14, 1:3) to yield the title compound (25.782 g). (Found C, 69.92; H, 8.18. C13H18O3 requires C, 70.25; H, 8.16).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:30][C:31]1[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=[N:35][C:36]=1[Cl:37]>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:38]([C:33]3[CH:34]=[N:35][C:36]([Cl:37])=[C:31]([Br:30])[CH:32]=3)(=[O:40])=[O:39])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2N
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Yield: 54.8 %

Procedure:
Starting with (5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (example 1-1, method A, 3rd step) (2.0 g, 7.2 mmol), diisopropylethylamine (2.0 g, 15.5 mmol) and 5-bromo-6-chloro-pyridine-3-sulfonyl chloride (2.1 g, 7.3 mmol), using the method analogous to the one for example 1-1, method A, 4th step, [5-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (2.1 g, 55%) was obtained. MS cald. for C21H24BrClN2O5S 530, obsd. 531 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([OH:8])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.C([Li])CCC.[CH2:37]1[O:42][C:40](=[O:41])[NH:39][C@@H:38]1[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([N:39]1[CH:38]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:37][O:42][C:40]1=[O:41])=[O:8]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(CCc1ccccc1)CC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the compound of example 49 (2.51 g, 10.62 mmol) in anhydrous THF (60 mL) and containing triethyl amine (1.8 mL, 12.74 mmol) at −70° C. was added drop wise trimethylacetyl chloride. After 15 minutes, the reaction mixture was placed in an ice bath and stirred for 45 minutes after which time, the reaction mixture was cooled to −78° C. In a separate flask, n-butyl lithium (2.5M in hexanes, 43 mL, 10.62 mmol) was added to a solution of R-4-benzyl-2-oxazolidinone in anhydrous THF at −78° C. After 15 minutes of stirring, this mixture was transferred by cannula to the former solution. The resultant mixture was stirred for 20 minutes at −78° C. followed by an additional 2 h in an ice bath. The reaction was quenched by the addition of a saturated solution of ammonium chloride. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted with brine, saturated sodium hydrogen carbonate, brine, and water, respectively. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude material was flashed using 30% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 300 MH: 1.89(m, 1H); 2.05(m, 1H); 2.75(m, 3H); 3.00(m, 1H); 3.68(m, 3H); 3.75(s, 3H); 4.18(m, 2H); 4.65(m, 1H); 7.21(m, 5H), 7.33(m, 5H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([NH2:30])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][CH2:36][C:37]([O:39][CH2:40]C)=[O:38].O>CN(C=O)C>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:14]=3)=[CH:11][C:10]([S:27]([NH:30][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNS(=O)(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
To a solution of compound 1 (1.0 g, 2.25 mmol) in dry DMF (10 mL) was added NaH (60%, 92 mg, 2.3 mmol) at 0° C. and the mixture was stirred for 10 min, ethyl 3-bromopropanoate (410 mg, 2.25 mmol) was added and stirred at rt for 5 h. Water was added and the solution was extracted with EA. The organic layer was washed with brine twice, concentrated and purified by CC (PE/EA=5/1) to give compound 38 (400 mg, 34%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]([NH:5][NH:6][C:7]([NH2:9])=[O:8])=O.[OH-].[K+].Cl>>[C:2]([C:3]1[NH:5][NH:6][C:7](=[O:8])[N:9]=1)([CH3:11])([CH3:10])[CH3:1]
Reactant: CC(C)(C)C(=O)NNC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1nc(=O)[nH][nH]1
Temperature: 100 °C
Yield: 45 %

Procedure:
To the obtained white powder of trimethylacetylsemicarbazide was added 1500 ml of a 5% aqueous potassium hydroxide solution, and the mixture was heated to 100° C. with stirring. After the contents were completely dissolved, the solution was further heated at 100° C. for one hour, and the reaction mixture was cooled and then neutralized by an addition of conc. hydrochloric acid. The white precipitates formed were collected by filtration, washed with water, and then dried under reduced pressure to give 64 g of 3-tert-butyl-1H-1,2,4-triazole-5-one as white powder (yield 45%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:23]1[CH:27]=[CH:26]N=C1)=O.C(N(CC)CC)C.Cl.C(N)C>C(#N)C>[C:1]1([CH:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH2:9][CH:10]([C:12]([NH:23][CH2:27][CH3:26])=[O:14])[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Yield: 114 %

Procedure:
To a solution of 7.5 g (28 mmole) of 1-(diphenylmethyl)azetidine-3-carboxylic acid in 75 ml of acetonitrile was added 6.0 g (37 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated at 60° C. for two hours and successively treated with 3.1 g (30.8 mmole) of triethylamine and 2.52 g (30.8 mmole) of ethylamine hydrochloride. The reaction was stirred at 60° C. for an additional hour, the solvent evaporated in vacuo and the residue dissolved in chloroform. After washing with water and drying over magnesium sulfate, the chloroform layer was evaporated in vacuo to give 9.4 g of 1-(diphenylmethyl)-N-ethyl-3-azetidinecarboxamide, mp 91°-93° C.
Reaction SMILES: CS(O[C@@H:6]1[C:23]2[C@:18]([CH3:25])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[C@@H:7]1OS(C)(=O)=O)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+].C(O)(=O)C>CO>[N:32]([C:6]1[C:23]2[C@:18]([CH3:25])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1C(N=[N+]=[N-])=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Conversion of 6α,7α-dihydroxy-4-androstene-3,17-dione to the corresponding 6α,7α-dimethanesulfonate ester by treatment with methanesulfonyl chloride in pyridine in a manner similar to that described in Example 22B followed by treatment of the resulting 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in dimethylformamide in a manner similar to that described in above Example 22C does not yield an identifiable amount of 6-azido-4,6-androstadiene-3,17-dione. Similarly, treatment of 6α,7α-dimethanesulfonyloxy-4-androstene-3,17-dione with sodium azide in aqueous methanol in the presence of acetic acid in a manner similar to that described in Example 6, does not yield an identifiable quantity of 6-azido-4,6-androstadiene-3,17-dione.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C>[CH3:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:45][CH:44]=1
Reactant: Cc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cc2cc(O)c(=O)[nH]n2)cc1

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-methylphenyl)methyl]pyridazine (Intermediate 56) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptanes.
Reaction SMILES: [BrH:1].C1(O[CH2:9][C:10]2[CH:17]=[C:16]([C:18]3([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]3[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=2[C:12]#[N:13])C=CC=CC=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:1][CH2:9][C:10]1[CH:17]=[C:16]([C:18]2([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]2[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to a solution of 2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 ml). The resulting solution is stirred at 55° C. for 6 h and then cooled in an ice-bath. The reaction mixture is neutralized with chilled aqueous potassium carbonate solution, and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate/cyclohexane (1:5), and the precipitate is separated by filtration and dried at 50° C. to give the pure product.