Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Step 1. To a mixture of 4-(4-hydroxyphenyl)cyclohexanone (19.0 g, 0.1 mol) and triethylamine (40.4 g, 0.4 mol) in CH2Cl2 (700 ml) at 0° C. was added dropwise acetyl chloride (15.7 g, 0.2 mol). After the addition was finished, the reaction mixture was warmed to rt and stirred overnight. The reaction mixture was washed with water and brine, dried over MgSO4, and concentrated. The crude product was crystallized from 95% aq. ethanol to afford 4-(4-acetoxyphenyl)-cyclohexanone (17.6 g, 76%) as a colorless solid. mp 104-106° C. (95% aq. ethanol); 1H NMR (500 MHz, CDCl3) δ 1.88-1.98 (m, 2H), 2.20-2.26 (m, 2H), 2.48-2.54 (m, 4H), 2.30 (s, 3H), 3.00-3.07 (m, 1H), 7.03 (d, J=8.7 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H). Step 2. A solution of O-methyl 2-adamantanone oxime (16.0 g, 89 mmol) and 4-(4-acetoxyphenyl)cyclohexanone (13.8 g, 59 mmol) in cyclohexane (400 ml) and CH2Cl2 (100 ml) was treated with ozone according to the general procedure. The crude product was triturated with ethanol (200 ml) to afford adamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane (16.4 g, 70%) as a colorless solid. mp 149-151° C. (ethanol); 1H NMR (500 MHz, CDCl3) δ 1.64-2.08 (m, 22H), 2.29 (s, 3H), 2.50-2.60 (m, 1H), 7.00 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H). Step 3. A mixture of adamantane-2-spiro-3′-8′-(4′-acetoxyphenyl)-1′,2′,4′-trioxaspiro[4.5]decane (16.4 g, 41 mmol) and 15% aq. KOH (65 ml) in THF/MeOH (1:2, 500 ml) was heated at 50° C. for 4 h. After being cooled to rt, the reaction mixture was concentrated to 70 ml, diluted with water (70 ml), and acidified with acetic acid (30 ml). The precipitate was collected by filtration to afford trioxolane OZ288 (14.36 g, 98%) as a colorless solid. mp 136-138° C.; 1H NMR (500 MHz, CDCl3) δ 1.56-2.18 (m, 22H), 2.41-2.58 (m, 1H), 5.90 (br s, 1H), 6.76 (d, J=8.5 Hz , 2H), 7.05 (d, J=8.5 Hz, 2H); 13C NMR (125.7 MHz, CDCl3) δ 26.49, 26.89, 31.65, 34.75, 34.80, 36.41, 36.81, 42.05, 108.46, 111.35, 115.22, 127.71, 138.03, 154.26. Anal. Calcd for C22H28O4: C, 74.13; H, 7.92. Found: C, 73.90; H, 7.85.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[NH:15]1[CH2:25][CH2:24][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16]1>>[CH2:22]([O:21][C:19]([CH:18]1[CH2:24][CH2:25][N:15]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:16][CH2:17]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: CCOC(=O)C1CCN(CCCc2ccc3c(n2)COC3=O)CC1
Yield: 82.7 %

Procedure:
In a process similar to that described in Preparation 8 3-(5-oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and ethyl isonipecotate (62 μL, 0.4 mmol) are reacted to provide the title compound as white solid (110 mg, 83%).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])[CH2:35][NH:34][C:33]1=[S:38])[CH3:28].N1CCCCC1>ClCCl>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:17]/[C:15]2[O:16][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=3)=[CH:13][CH:14]=2)/[NH:34][C:33]1=[S:38])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Reactant: CCOC(=O)CN1C(=O)CNC1=S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CC(=O)OCC)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (10 mg, 0.022 mmol) synthesized by the same method as in Example 4 and ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate (4.4 mg, 0.022 mmol) synthesized by the same method as in Example 2 were dissolved in dichloromethane (3 mL), piperidine (5 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give labeling precursor 2 in a yield of 11 mg (74.0%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Br)(=[O:3])[CH3:2].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:32]1[C:28]([CH3:27])=[N:29][O:30][C:31]=1[CH3:36])(=[O:3])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1-c1c(C)noc1C

Procedure:
By carrying out the operation analogously to example 177, starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of a pink powder (yield=30%).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][O:4][CH3:5].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: COCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COCC(C)Oc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (260 mg) in dry methanol (10 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (4.0 ml). The reaction was left to stir at room temperature for 3 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. The residue was taken up in water (15 ml) and the solid filtered and washed with water (2×5 ml). The solid was dried en vacuo (60° C.) for 30 minutes. This afforded the title compound as an off-white solid (70 mg).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([F:19])=[C:12]([O:20][CH2:21][CH3:22])[CH:11]=1)(C)C)(C)(C)C>CO>[CH2:21]([O:20][C:12]1[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]=1[F:19])[CH3:22]
Reactant: CCOc1cc(CO[Si](C)(C)C(C)(C)C)cc(OCC)c1F
Solvent: CO
Product: CCOc1cc(CO)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of tert-butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane (1.20 g, 3.65 mmol, 1.0 equiv) in methanol (8 mL) was added Dowex 50W-X8 (0.33 g, cation exchange resin) and the reaction mixture stirred under Ar at rt for 22 h. The resin was removed by filtration and the reaction mixture concentrated by evaporation under reduced pressure yielding the title compound in quantitative yield (0.78 g). 1H NMR (400 MHz, CDCl3): δ1.34 (t, J=7.0 Hz, 6H), 1.57 (t, J=5.4 Hz, 1H), 4.01 (q, J=7.0 Hz, 4H), 4.51 (d, J=5.4 Hz, 2H), 6.51 (d, J=6.8 Hz, 2H). MS (EI): 214.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:24][CH3:25])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:24]([CH3:25])=[O:39])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(4-fluorobenzyl)pyrimidine-5-carboxamide (206 mg, 0.46 mmol) was dissolved in 20 mL dichloromethane, m-CPBA (80 mg, 0.46 mmol) was added and reacted at room temperature for 12 h, the reaction solution was washed with water after the reaction is complete, extracted with dichloromethane, the organic layer was dried, dried by rotation to obtain yellow solid, the product was directly used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].N12CCCN=C1CCCCC2.Cl.Cl.[CH:34]12[NH:42][CH2:41][CH:38]([NH:39][CH2:40]1)[CH2:37][CH2:36][CH2:35]2>C(#N)C>[Cl:1][C:2]1[C:3]([N:39]2[CH2:40][CH:34]3[NH:42][CH2:41][CH:38]2[CH2:37][CH2:36][CH2:35]3)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A suspension of 1.0 g (3.34 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30 ml of acetonitrile, 1.52 g (10.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 0.72 g (3.62 mmol) of 6,8-diazabicyclo [3.2.2]nonane, dihydrochloride was heated under reflux for 3 hr, then stirred at room temperature overnight. The precipitate was removed by filtration and washed with acetonitrile and ether to give 0.82 g of the title compound, mp 217°-220° C.
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[N:1]1([C:8]2[C:9]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(benzo[b]thiophen-2-yl)quinoxaline-6-carboxylate (82 mg, 0.2 mmol) in methanol (15 mL) was added sodium hydroxide (80 mg, 2 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with HCl (3 N) and filtered to give 3-(azepan-1-yl)-2-(benzo[b]thiophen-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (70.1 mg, 88%).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH:18]([CH3:19])[CH:17]([CH2:20][CH3:21])[CH2:16][CH:15]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[O:14]2)[CH2:8][C:7]1=[O:27])(=O)[CH2:2][CH2:3][CH3:4].Cl.[Cl:29][CH:30]=[CH:31][CH2:32][O:33][NH2:34]>C(O)C.C([O-])(=O)C.[Na+]>[Cl:29][CH:30]=[CH:31][CH2:32][O:33][NH:34][CH2:4][CH2:3][CH2:2][CH:1]=[C:6]1[C:7](=[O:27])[CH2:8][CH:9]([CH:13]2[CH:18]([CH3:19])[CH:17]([CH2:20][CH3:21])[CH2:16][CH:15]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[O:14]2)[CH2:10][C:11]1=[O:12]
Reactant: NOCC=CCl
Reactant: CCCC(=O)C1C(=O)CC(C2OC(OCC(C)C)CC(CC)C2C)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC1CC(OCC(C)C)OC(C2CC(=O)C(=CCCCNOCC=CCl)C(=O)C2)C1C
Temperature: 25 °C

Procedure:
10.2 parts by weight of 2-butyryl-5-(3-methyl-4-ethyl-6-isobutoxytetrahydropyran-2-yl)-cyclohexane-1,3-dione were dissolved in 100 parts by volume of ethanol, and 2.42 parts by weight of sodium acetate and 3.86 parts by weight of O-(3-chloroallyl)-hydroxylamine hydrochloride were added. The mixture was stirred for several hours at room temperature and then poured into ice-water, and the resulting mixture was extracted with methylene chloride. The methylene chloride phase was evaporated off, leaving 11.1 parts by weight of 2-(3-chloroallyloxyaminobutylidene)-5-(3-methyl-4-ethyl-6-isobutoxytetrahydropyran-2-yl)-cyclohexane-1,3-dione as a yellow oil of refractive index nD22 1.5129.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:21])[N:9]([CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](O)(=[O:31])[CH3:30]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[C:29]([N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([N:9]2[C:10]([OH:21])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:12](=[O:13])[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]2=[O:28])[CH2:23]1)(=[O:31])[CH3:30]
Reactant: O=C(O)CNC(=O)c1c(O)n(C2CCCNC2)c(=O)n(C2CCCCC2)c1=O
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCCC(n2c(O)c(C(=O)NCC(=O)O)c(=O)n(C3CCCCC3)c2=O)C1
Yield: 31 %

Procedure:
A solution of N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine (500 mg, 1.26 mmoles) in acetic acid (5.0 mL) and acetic anhydride (5.0 mL) was heated at 130° C. for 2 hours. The mixture was cooled, diluted with ethyl acetate and washed with 1 molar hydrochloric acid (×3), dried and evaporated. Flash chromatography (dichloromethane to 4% methanol-0.1% acetic acid in dichloromethane) and recrystallization from ethanol-water gave the title compound (170 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.17 (s, 1 H), 4.46-4.73 (m, 2 H), 4.25-4.46 (m, 1H), 4.13 (d, J=5.56 Hz, 2 H), 3.67-3.92 (m, J=4.55 Hz, 1 H), 3.24-3.43 (m, 1 H), 2.94 (t, J=12.63 Hz, 1 H), 2.34-2.48 (m, 1 H), 2.25 (m, 2 H), 1.97, 2.02 (2×s, 3 H), 1.69-1.87 (m, 4 H), 1.62 (m, 3 H), 1.41-1.57 (m, 1 H), 1.19-1.37 (m, 2 H), 0.97-1.18 (m, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: Clc1ccc(Cl)nc1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(Oc4ccc(Cl)cn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2,5-dichloro-pyridine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[CH2:12][C@@H:11](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[N-:32]=[N+:33]=[N-:34].[Li+]>CS(C)=O>[N:32]([C@@H:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]2([CH3:14])[CH2:12]1)[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](OS(=O)(=O)c3ccc(C)cc3)C[C@@H]12
Agent: [Li+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@H](N=[N+]=[N-])C[C@@H]12

Procedure:
3.3 g (7.5 mmol) of 3-methoxy-16β-tosyloxy-estra-1,3,5(10)-triene and 0.99 g (15.7 mmol) lithium azide in 66 ml of DMSO are reacted as described above. Yield: 2.15 g (92%), F=80-89° C., after recrystallization from acetone: F=89-92° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH3:25])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH3:25])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: COc1cc(Cl)ccc1CO
Product: COc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-methoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.89 (3H, s), 5.22 (2H, s), 5.78 (1H, d, J=2.0 Hz), 6.92 (1H, d, J=2.0 Hz), 6.95-6.98 (1H, m), 7.33-7.35 (1H, m), 7.39 (1H, dd, J=1.2, 5.2 Hz), 7.57-7.58 (1H, m), 8.06 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O2, 341. Found, 341.
Reaction SMILES: [BrH:1].N[C@@H:3]([C@@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5].N([O-])=O.[Na+]>Br>[Br:1][C@@H:3]([C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C(=O)OC)[C@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: CC[C@@H](C(=O)OC)[C@H](Br)C(=O)O
Temperature: -9 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of crude amino acid salt (2S,3S)-2-amino-3-(methoxycarbonyl)pentanoic acid hydrobromide (19.6 g) of Example 7 in aqueous hydrobromic acid (2.5N), cooled to -9° C. with an ice water-salt-acetone bath, was added sodium nitrite (10.0 g, 144.9 mmol) in small portions over a 1.5 h period, keeping the internal temperature (measured by electronic internal temperature probe) below -7° C. The reaction mixture was stirred for 2 h in the cooling bath after the addition was complete, then it was extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride (2×250 mL), dried (MgSO4), and concentrated in vacuo to give the bromoacid which slowly solidified to a waxy solid (13.0 g).
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:30][C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: COc1ccc(O)cc1OC
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (2.820 g, 8.70 mmol), 3,4-dimethoxy phenol (1.347 g, 8.74 mmol) and cuprous oxide (647 mg, 4.52 mmol) in 2,4,6-collidine (20 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 106.85° C. (DSC).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:21]I.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:21])[C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Nc2cccc(F)c2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(C(=O)O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH 60% dispersed in mineral oil (0.024 g; 0.611 mmol) was added to a solution of methyl 4-(3-fluorophenylamino)benzoate in THF (3 mL). After stirring the resulting solution for 10 minutes methyl iodide (0.062 mL; 0.994 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with water, acidified with a 6N solution of hydrochloride acid and extracted with ethyl acetate. The organic layer was dried to yield 0.119 g (quantitative) of the title compound as a brown solid. The compound was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=3[F:24])[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[CH:42]=[C:41]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=4[F:24])[CH:11]=[C:10]([C:25]([F:28])([F:26])[F:27])[N:9]=3)[CH:3]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.105) (0.465 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as light yellow foam (0.54 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[O:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:41]4[CH2:42][CH2:43][CH:38]([N:35]5[CH2:36][CH2:37][O:32][CH2:33][CH2:34]5)[CH2:39][CH2:40]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CCC(N6CCOCC6)CC5)CC4=O)cc3)CC2)c(C)c1
Yield: 62.4 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and 4-morpholinopiperidine (44 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (85 mg) was obtained.