Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:28]2[N:29]=[CH:30][CH:31]=[N:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4nccn4)=C(C=O)C[C@@H]32)C1
Temperature: 80 °C
Yield: 31.9 %

Procedure:
A mixture of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) (2.0 g, 5.23 mmol), 1H-1,2,3-triazole (552 mg, 7.98 mmol) and K2CO3 (2.20 g, 15.95 mmol) in dry DMF (40 ml) was heated at 80° C. under N2 atmosphere for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-water (400 ml), and the resulting precipitate was filtered, washed with water, and dried to give a dirty white solid. This was subjected to flash chromatography, and on elution with pet. ether/EtOAc/Et3N, (6.7:3:0.3), gave firstly 3β-acetoxy-17-(2H-1,2, 3-triazol-2-yl)-16-formylandrosta-5,16-diene (Compound 15) (684 mg, 28%), mp 145-148° C. 1H NMR (300 MHz, CDCl3): δ 1.09 (3H, s, 18-Me), 1.26 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.61 (1H, m, 3α-H), 5.42 (1H, d, J=4.2 Hz, 6-H), 7.85 (2H, s, 4′ and 5′-H) and 10.55 (1H, s,-16-CHO). Analysis calculated for C24H31O3N3: C, 70.37; H, 7.63; N, 10.27. Found: C, 70.30; H, 7.95; N, 9.87. Further elution with pet. ether/EtOAc/Et3N, (6:4:0.3) gave 3β-acetoxy-17-(1H-1,2,3-triazol-1-yl)-16-formylandrosta-5,16-diene (Compound 16) (1.48 g, 62%), mp 215-217° C. 1H NMR (300 MHz, CDCl3): δ 1.08 (3H, s, 18-Me), 1.18 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.63 (1H, m, 3α-H), 5.43 (1H, d, J=4.2 Hz, 6-H), 7.85 (2H, s, 4′ and 5′-H) and 9.94 (1H, s, 16-CHO). Analysis calculated for C24H31O3N3: C, 70.37; H, 7.63; N, 10.27. Found: C, 70.37; H, 7.86; N, 10.10.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:29])=[N:9]2)=[CH:4][CH:3]=1.C[O:31]CCOC.O1CCCC1.[OH-].[K+]>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:20]([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]([OH:31])=[O:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCOC
Reactant: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Temperature: 30 °C
Reaction time: 34 h
Yield: 85 %

Procedure:
To a reactor was charged racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone (170 kg), 1,2-dimethoxyethane (730 L), tetrahydrofuran (THF, 990 L). The slurry was heated to 30° C. and a solution of potassium hydroxide (140 Kg) in water (1730 L) was added. The slurry was stirred at 34° C. for 34 hours. The solution was cooled to 20° C. and the lower aqueous layer was removed and replaced with water (1000 L). The solution was adjusted to pH 9.0 with 4N hydrochloric acid. The solution was vacuum distilled at 30° C. to remove the THF. Water (550 L) was added and the pH of the reaction was adjusted to 11.5 with 2N potassium hydroxide. The solution was filtered to remove residual racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone. To the liquors was added methylene chloride (1200 L) and the pH was adjusted to 1.4 with 4N HCl. The aqueous layer was removed. The organic layer was washed with water (700 L) and the water was discarded. The organic layer was concentrated under vacuum and replaced with methanol (500 L). The slurry was cooled to 10° C., water was added (500 L), and the mixture was cooled to 0° C. The resulting precipitate was isolated by filtration and dried under vacuum at 50° C. to afford 150 kg (85%) of racemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoic acid as a white solid. DCI/MS: M+H+ at 426, 100%. M.P. 173-4° C. UV maxima at 236 nm, 268 nm, and 353 nm.
Reaction SMILES: [H-].[Na+].N#N.[CH2:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:14]1[N:22]=[C:21]([NH2:23])[N:20]=[C:19]2[C:15]=1[NH:16][CH:17]=[N:18]2>C1(C)C=CC=CC=1>[CH2:5]([O:12][C:14]1[N:22]=[C:21]([NH2:23])[N:20]=[C:19]2[C:15]=1[NH:16][CH:17]=[N:18]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 115 °C
Reaction time: 0.17 h

Procedure:
60% Sodium hydride in mineral oil (2.36 g, 0.059 moles) was charged to a 500 mL 3-neck flask equipped with magnetic stirring, temperature probe, condenser, and N2 inlet. Toluene (250 mL) was added. Benzyl alcohol (50 mL) was added dropwise over 30 minutes. After addition of benzyl alcohol, the reaction was stirred 10 minutes. Then 6-chloro-2-aminopurine (5.00 g, 0.029 moles) was added and the reaction mixture was heated to reflux (115° C.) for 4.5 hours. The reaction mixture was filtered hot through a coarse glass fritted funnel and 11.65 g of wet off-white solids were obtained. The wet solids were triturated with CH2Cl2 (100 mL) and water (100 mL). After 10 minutes of stirring the solids had dissolved. The aqueous layer was separated and the pH was lowered to 9 over 3 minutes with 6 M HCl. A white solid precipitate formed. The slurry was filtered, washed with water (50 mL), and dried (in vacuo at 50° C.) to a constant weight to provide the desired product as off-white crystals (5.15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[O:18][CH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28].C(N(C(C)C)CC)(C)C>[Cu]I.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:23]1[CH2:24][CH2:25][CH:20]([CH2:19][O:18][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:30]#[C:29][C:27]([OH:31])([CH3:28])[CH3:26])[CH:3]=3)[NH:8][C:7](=[O:12])[C:6]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22]1
Reactant: O=c1[nH]c2ccc(Br)cc2c(OCC2CCOCC2)c1-c1cccs1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C#Cc1ccc2[nH]c(=O)c(-c3cccs3)c(OCC3CCOCC3)c2c1
Temperature: 100 °C

Procedure:
A 5 mL microwave vial was charged with a magnetic stir bar, 6-bromo-4-(tetrahydro-2H-pyran-4-ylmethoxy)-3-(thiophen-2-yl)quinolin-2(1H)-one (22 mg, 52 mop, copper(I) iodide (1.0 mg, 5.0 mop, and bis(tri-t-butylphosphine) palladium(0) (1.0 mg, 3.0 μmol). The vessel was sealed. The contents of the vessel were dried under high vacuum, and flushed with nitrogen. Acetonitrile (500 μL) was added under nitrogen followed by addition of 2-methyl-3-butyn-2-ol (18 mg, 210 μmol), and diisopropylethyl amine (46 μL, 260 μmol). The reaction was heated to 100° C. in an oil bath for 3 h. The crude product was purified by reverse-phase chromatography to yield 4-(tetrahydro-2H-pyran-4-ylmethoxy)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(thiophen-2-yl)quinolin-2(1H)-one as off white solid. LCMS (M+H)=423.9. 1H NMR (400 MHz, CDCl3) 11.0 (s, 1H), 7.90 (s, 1H), 7.84 (d, 1H), 7.52 (m, 2H), 7.24 (1H), 7.18 (t, 1H), 4.00 (dd, 2H) 3.65 (d, 2H), 3.45 (t, 2H), 2.15 (m, 1H), 1.75 (d, 2H), 1.65 (s, 6H), 1.50-1.40 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:12])[CH:3]=1.[CH:13](OCC)(OCC)OCC.[N-:23]=[N+:24]=[N-:25].[Na+]>C(O)(=O)C>[CH3:12][C:4]1[CH:3]=[C:2]([N:1]2[CH:13]=[N:25][N:24]=[N:23]2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(N)ccc1CC(=O)O
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnn2)ccc1CC(=O)O
Temperature: 0 °C

Procedure:
To a solution of (4-amino-2-methylphenyl)acetic acid (0.10 g, 0.61 mmol) and triethyl orthoformate (0.16 ml, 0.97 mmol) in acetic acid (1 ml) was added sodium azide (0.059 g, 0.91 mmol). The resulting mixture was heated to reflux for 4 hours. The mixture was poured into ice water and the resulting solid collected by filtration and dried, under vacuum to provide [2-methyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid. LC-MS (IE, m/z): 219 [M+1]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[CH2:7][CH2:8][N:9]=2)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cc1ccc(Oc2ccccc2)cc1)NCCC1=CCCCC1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(Oc2ccc(CC3=NCCC4=C3CCCC4)cc2)cc1

Procedure:
A mixture of 2.5 g (0.01 mol) N-[2-(1-cyclohexen-1-yl)ethyl]-4-phenoxyphenyl acetamide, 5.0 ml of POCl3 and 20 ml of toluene was heated at reflux under nitrogen for 2 hrs. After evaporation of the solvent and excess reagent there was obtained (±)-1-(p-phenoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline as residue. The residue was triturated with pet ether (2×10 ml). The pet ether insoluble hexahydro compound was dissolved in methanol and immediately reduced by portionwise addition of 1.0 g of sodium borohydride. The reaction mixture was stirred at room temperature for 4 hrs. The methanol was distilled off and the residue was partitioned between ether (60 ml) and dilute aqueous ammonium hydroxide. The ether solution was washed with water, dried and evaporated to give 1.6 g (69%) of crude (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline.
Reaction SMILES: Cl[C:2]([CH3:12])([CH3:11])[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O-])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Na+].O>CS(C)=O>[CH:5]1([C:3]([C:2]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])([CH3:12])[CH3:11])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(Cl)C(=O)C1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(C)(C)C(=O)C2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 27.4 %

Procedure:
A solution of 2-chloro-1-cyclohexyl-2-methyl-1-propanone (30.0 g, 0.16 mole) and sodium p-toluenesulfonate (30.0 g, 0.17 mole) in dimethylsulfoxide was reacted with stirring at 60° C. for 20 hours. The reaction mixture was poured into cold H2O, and stirred at 0°-5° C. for 1 hour. The precipitate was filtered, washed with H2O and dried. The crude solid (18 g) was recrystallized from n-hexane/benzene to give 13.5 g of 2-cyclohexylcarbonyl-2-(p-toluenesulfonyl)propane as white needles.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH2:10])=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(F)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.7 %

Procedure:
6.5 g of 2-[3-(4-fluoro-2-nitrophenoxy)propyl]Isoindole-1,3-dione was suspended in ethanol (140 ml), and hydrazine hydrate (3.0 ml) was added to the resulting suspension. The mixture was stirred for 3.5 hours while heating under reflux. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. 13 ml of 5N sodium hydroxide aqueous solution was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 4.03 g of oily red orange 3-(4-fluoro-2-nitrophenoxy)propylamine (yield: 100%).
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[F:20])C1C=CC=CC=1.CO>[C].[Pd].C(OCC)(=O)C>[F:20][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:18][CH3:19])[C:9]=1[OH:8])[C:13]([OH:15])=[O:14]
Reactant: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)O)cc(F)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4-benzyloxy-3-fluoro-5-methoxybenzoic acid were added 20 ml of methanol, 20 ml of ethyl acetate and 50 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. Then, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 4.5 g of 3-fluoro-4-hydroxy-5-methoxybenzoic acid represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([N+:13]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([NH2:13])[CH:5]=1
Reactant: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNc1ccc(C(=O)OC)cc1N
Yield: 89 %

Procedure:
3-Amino-4-ethylamino-benzoic acid methyl ester (6.4 g) was prepared by following General Procedure B starting from 4-ethylamino-3-nitro-benzoic acid methyl ester (8.3 g) and Pd/C (20% by weight, 170 mg) in MeOH:EtOAc (1:1, 50.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(O)(=O)C[SH:18].[C:21]([O:24]CC)(=O)[CH3:22]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:14]1[C:15]2[CH:2]([CH2:22][C:21]([OH:24])=[S:18])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)CS
Reactant: OC1c2ccccc2Oc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OC(=S)CC1c2ccccc2Oc2ccccc21
Yield: 72 %

Procedure:
A solution of 9-hydroxyxanthene (Aldrich) (1.0 g, 5.0 mmol), thioglycolic acid (42 μL, 6.0 mmol), and ρ-toluenesulfonic acid monohydrate (10 mg) in 10 mL of toluene is stirred for 30 minutes. The reaction is diluted with ethyl acetate and washed 3 times with water and once with brine. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid is chromatographed twice on silica gel eluting with methanol:chloroform (5:95) to give 1.0 g (72%) of xanthen-9-yl-thioacetic acid: melting point 131°-132° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.C(N(CC)CC)C.Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following substantially the procedure of Schaeffer, et al. supra but with minor modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4 g) was added with stirring to a dry solution of 6-chloropurine (3.1 g) and triethylamine (6.5 ml) in dimethylformamide (50 ml). The reaction was exothermic, immediately precipitating triethylamine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated on a rotary evaporator at 70° C. The remaining thick amber oil was dissolved in the minimum amount of benzene and purified by column chromatography using a silica gel column. Benzene elution removed a trace of an unidentified material. Elution with ether first removed a small amount of ethylene glycol monobenzoatc and then 6-chloro-9-(2-benzoyloxyethoxymethyl)purine. Recrystallization from ether gave a white material, m.p. 108.5°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN1CCCC1=O>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:6](=[O:8])[C:5]5[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:45]=[CH:44][CH:43]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: COc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 42.5 %

Procedure:
Using 3-methoxybenzoic acid (48 mg, 0.32 mmol), oxalyl chloride (32 μL, 0.37 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (49 mg, 43%) was obtained as a white powder.
Reaction SMILES: C([Si](C)(C)[O:4][Si:5]([CH:8]=[CH2:9])([CH3:7])[CH3:6])=C.[Cl:12][Si:13]([Cl:16])(Cl)Cl.C(N(CC[CH2:28][CH3:29])CCCC)CCC>C(Cl)Cl>[CH:28]([Si:5]([CH3:7])([CH3:6])[O:4][Si:13]([Cl:16])([Cl:12])[O:4][Si:5]([CH:8]=[CH2:9])([CH3:6])[CH3:7])=[CH2:29]
Reactant: CCCCN(CCCC)CCCC
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: ClCCl
Product: C=C[Si](C)(C)O[Si](Cl)(Cl)O[Si](C)(C)C=C
Temperature: 25 °C
Reaction time: 116 h

Procedure:
About 1 ml of a 25% solution of phosphonitrile chloride in methylene chloride is added to a mixture containing 278 g (1.5 mol) of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane and 85 g (0.5 mol) of tetrachlorosilane. After the mixture has been stirred at room temperature for 116 hours, 1.1 ml of tri-n-butylamine are added, and the reaction mixture stirred for an additional 30 minutes and then subsequently fractionally distilled. At 45° to 52° C. and at 3 mbar, 85 g of 1,5-divinyl-1,1,5,5-tetramethyl-3,3-dichlorotrisiloxane are obtained, but no 1,5-divinyl-1,1,5,5-tetramethyl-3-chloro-3-vinyldimethylsiloxytrisiloxane.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C@@H:18]1[C@@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:21]([OH:34])[CH2:20][C@@H:19]1[OH:35]>C(Cl)(Cl)Cl.O1CCCC1>[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH:15]([Br:1])[CH:16]1[O:35][C@H:19]2[CH2:20][C@@H:21]([OH:34])[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:18]2[CH2:17]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Yield: 70.4 %

Procedure:
By proceeding as described in Example 1 but using 800 mg of N-bromosuccinimide and 1.47 g of (5Z,13E)-(9α,11α,15R)-9,11,15-trihydroxy-16,16-dimethylprosta-5,13-dienoic acid methyl ester dissolved in a mixture of 40 ml of chloroform and 4 ml of tetrahydrofuran, there was obtained 1.24 g of the title compound having the following physical characteristics:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[C:24]([CH3:26])[C:8]2[NH:9][C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Cl:27][C:28]1[S:32][C:31]([C:33]2[O:37][N:36]=[C:35]([CH2:38]OS(C)(=O)=O)[CH:34]=2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[S:32][C:31]([C:33]2[O:37][N:36]=[C:35]([CH2:38][N:9]3[C:8]4[C:24]([CH3:26])=[CH:25][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=4[N:11]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[CH:34]=2)=[CH:30][CH:29]=1.[Cl:27][C:28]1[S:32][C:31]([C:33]2[O:37][N:36]=[C:35]([CH2:38][N:11]3[C:7]4[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:25]=[C:24]([CH3:26])[C:8]=4[N:9]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:21][CH2:22]4)[CH2:16][CH2:15]3)[CH:34]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(C)c2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc2c1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(Cl)s2)on1
Product: Cc1cc(C(=O)O)cc2c1nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Product: Cc1cc(C(=O)O)cc2nc(C(=O)NC3CCN(C4CC4)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c12

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-7-methyl-1H-benzoimidazole-5-carboxylic acid and 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-7-methyl-3H-benzoimidazole-5-carboxylic acid were prepared by a procedure according to example 81 starting from 200 mg (0.56 mmol) 2-(1-Cyclopropyl-piperidin-4-ylcarbamoyl)-7-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester and 164.8 mg (0.56 mmol) methanesulfonic acid 5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl ester. Hydrolysis of the resulting esters by treatment with LiOH and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccc(F)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.47 mmol) and pyridine (148 mg, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added a solution of 3-fluorobenzene-1-sulfonyl chloride (92 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous Sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 478.90.