Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[CH2:35][CH2:36][NH2:37]>ClCCl>[F:31][C:32]1[CH:33]=[C:34]([CH2:35][CH2:36][NH:37][C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:38]=[CH:39][CH:40]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1cccc(F)c1)c1ccc(Cl)nn1
Reaction time: 0.25 h
Yield: 37.8 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (0.31 g, 1.94 mmol) in dichloromethane (15.5 mL) was added diisopropylethylamine (0.73 mL, 4.19 mmol), followed by 1-hydroxybenzotriazole monohydrate (0.28 g, 2.1 mmol) and 1-(3-dimethylamino)propyl-3-ethylcarbodiimide (0.37 mL, 2.1 mmol). The resulting mixture was stirred for 15 minutes, followed by the addition of 3-fluorophenethylamine (0.28 mL, 2.1 mmol). After stirring for 27 hours at ambient temperature, the reaction mixture was diluted with dichloromethane (200 mL), washed with water (4×25 mL), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography eluted with dichloromethane:ethyl acetate (2:1) afforded the product as a white powder (0.205 g). 1H NMR (400 MHz, CDCl3) δ 8.26, 8.12, 7.67, 7.28-7.23, 6.95-6.89, 3.80-3.75, 2.95.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:5][C:4](=[O:11])[CH:3]=1.C(NN)(C)(C)C.C(CC(OCC)=O)#N.[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH:30]=O.[C:36]1(=O)[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]1>C(O)C>[Br:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:3]3[C:4](=[O:11])[NH:5][N:6]([C:7]([CH3:8])([CH3:10])[CH3:9])[C:2]=3[NH:1][C:36]3[CH2:40][CH2:39][C:38](=[O:41])[C:37]2=3)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: O=C1CCC(=O)C1
Reactant: CC(C)(C)n1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CC(C)(C)NN
Solvent: CCOC(=O)CC#N
Solvent: CCO
Product: CC(C)(C)n1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1
Temperature: 80 °C
Yield: 19 %

Procedure:
5-Amino-1-tert-butyl-1,2-dihydropyrazol-3-one (0.23 g, 1.5 mmol), prepared by the method of (A.Weisberger and A.Porter, J. Amer. Chem. Soc, (1944) 66, 1849) from tert butylhydrazine and ethyl cyanoacetate, 3-bromo-4-fluorobenzaldehyde (0.3 g, 1.5 mmol), and 1,3-cyclopentanedione (0.147 g, 1.5 mmol) in ethyl alcohol (3 mL) were heated at 80° C. for 2 days in a sealed tube. The solvent was evaporated under reduced pressure and the residue was chromatograhed on silica gel eluting with 10% ethanol/methylene chloride to provide 0.12 g of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 1.51 (s, 9H), 2.28 (m, 2H), 2.71 (m, 2H), 4.69 (s, 1H), 7.12 (m, 1H), 7.21 (t, 1H), 7.39 (dd, 1H), 9.43 (bs, 1H), 9.57 (s, 1H); MS (ESI−) m/z 420 (M−H)−; Anal. calcd for C19H19N3BrFO2: C, 54.17; H, 4.79; N, 9.97. Found: C, 54.17; H, 4.81; N, 9.85.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccn1
Temperature: 25 °C
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.027 mole) was added dropwise (slowly) to a stirred and chilled (10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]-pyridine-3-acetic acid (8.4 g, 0.025 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10° C.) solution of 2-aminopyridine (2.6 g, 0.028 mole) and triethylamine (5.4 g, 0.0053 mole) in anhydrous dimethyl formamide (100 ml). The reaction was stirred at room temperature overnight. Dimethylformamide (100 ml) was distilled off at 100 mm Hg. The residue was cooled, triturated in potassium bicarbonate solution (2×50 ml), and filtered. The filter cake was rinsed with water (2×50 ml) and recrystallized from ethanol-isopropyl ether to give 4.8 g (47%) of white solid, mp 191.5°-195° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[F:10])#[N:2].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:11])=[CH:5][C:4]=1[F:10])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1F
Temperature: 25 °C

Procedure:
To a solution of the product from Step C (22.2 g, 165 mmol) in 220 mL of carbontetrachloride was added N-bromosuccinimide (29.2 g, 164 mmol) and benzoylperoxide (1.1 g). The reaction was heated to reflux for 30 minutes, then cooled to room temperature. The solution was concentrated in vacuo to one-third the original volume, poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Analysis by 1H NMR indicated only partial conversion, so the crude material was resubjected to the same reaction conditions for 2.5 hours, using 18 g (102 mmol) of N-bromosuccinimide. After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane) to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:26])[CH:3]=1.[C:27](=O)([O-])O.[Na+]>COS(OC)(=O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:27])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=2[Cl:26])[CH:3]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)CN(C)c1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 15 step ii). (0.70 g) which was dissolved in dimethylsulphate (3 ml). Sodium hydrogen carbonate (0.355 g) was added and heated to 90 C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated under reduced pressure to give an oil. The residue was purified by chromatography on silica eluting with diethyl ether, yield 0.70 g.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.II.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].Cl>O1CCCC1>[C:6]1([CH2:5][CH2:4][CH2:3][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Yield: 469.5 %

Procedure:
Into a four-necked flask equipped with a thermometer, a dropping funnel and a stirrer, 4.8 g (0.2 mol) of magnesium flasks and 100 ml of anhydrous tetrahydrofuran were placed, followed by addition of a mixture of 4.0 g (20 mmol) of 1-bromo-3-phenylpropane and 10 ml of anhydrous tetrahydrofuran and a small quantity of iodine, heating of the flask contents to 60° C. and dropwise addition of a mixture of 35.8 g (0.18 mol) of 1-bromo-3-phenylpropane and 90 ml of anhydrous tetrahydrofuran at the same temperature. Thereafter, the mixture was stirred under reflux for 2 hours and then cooled to room temperature. The resulting mixture was added dropwise into a mixture consisting of 31.3 g (0.22 mol) of ethyl trifluoroacetate and 200 ml of anhydrous tetrahydrofuran. Thereafter, the mixture was stirred at -78° C. for 2 hours, then heated gradually to -50° C. and further stirred at the same temperature for 2 hours. Thereafter, 100 ml of 1N hydrochloric acid was added at -50° C., followed by heating to room temperature. The reaction mixture was extracted with 300 ml of ether and the formed organic layer was washed with water, a 5% sodium bicarbonate solution and brine successively in that order, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: toluene/hexane (1/4)) to give 20.3 g of 5-phenyl-1,1,1-trifluoropentane-2-one (14-1) in a yield of 47%.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:48]=[CH:47][C:40]([C:41]([NH:43][CH:44]2[CH2:46][CH2:45]2)=[O:42])=[CH:39][N:38]=1>>[CH:44]1([NH:43][C:41](=[O:42])[C:40]2[CH:47]=[CH:48][C:37]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[N:38][CH:39]=2)[CH2:46][CH2:45]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C(NC1CC1)c1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC3CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-N-cyclopropylnicotinamide following procedures analogous to those described in Example 486 Step 4. LC-MS Method tR=1.74 min, m/z=456.1; 1H NMR (CDCl3) 0.61 (m, 2H), 0.82 (m, 2H), 1.13 (s, 3H), 1.22 (s, 3H), 1.49 (d, 3H), 2.17 (m, 3H), 2.21 (m, 1H), 2.31 (m, 1H), 2.79 (m, 1H), 2.88 (m, 1H), 5.66 (m, 1H), 6.40 (s, 1H), 6.99 (d, 1H), 7.20-7.31 (m, 5H), 7.60 (d, 1H), 7.68 (d, 2H), 8.07 (d, 1H), 8.89 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][CH:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>CN1CCCC1=O>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:26]2[CH2:27][CH2:28][CH:24]([CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: c1ccc(CCC2CCNC2)cc1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)CCNC(=O)c1ccc(N2CCC(CCc3ccccc3)C2)nn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide (20 mg, 0.088 mmol) and 3-(2-phenylethyl)pyrrolidine (23 mg, 0.13 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was added Et3N (25 μL, 0.18 mmol) at room temperature. The mixture was stirred at 120° C. overnight. The reaction was then concentrated and the residue purified using a semi-prep HPLC/MS to give the title compound. MS (+ESI) m/z 367 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][O:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: CI
Reactant: CCOC(=O)c1ccc(N(C)CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N(C)CCOC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of ethyl 4-[(2-hydroxyethyl)(methyl)amino]benzoate (611 mg, 2.74 mmol) in DMF (10 ml) were added sodium hydride (60% in oil, 143 mg, 3.56 mmol) and methyl iodide (0.222 ml, 3.56 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (467 mg, 72%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[CH2:15](OC(O)O)C>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:2][CH:15]=[N:9][C:8]=12
Reactant: CCOC(O)O
Reactant: Nc1nccc(-c2cccs2)c1N
Agent: Cl
Product: c1csc(-c2ccnc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
Hydrochloric acid (35 wt %, 1.47 ml) was added to 2,3-diamino-4-(2-thienyl)pyridine (1.46 g, 7.61 mmol) and orthoformic acid ethyl ester (40.5 ml). This solution was stirred at room temperature for 3 days and then filtered. The residue was washed with ether to give 7-(2-thienyl)-3H-imidazo[4,5-b]pyridine (1.74 g, 96%).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9][Cl:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl-:10].[CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9][N+:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)CCl)cc1
Reactant: c1ccncc1
Product: CC(C)c1ccc(C(=O)C[n+]2ccccc2)cc1
Product: [Cl-]
Yield: 93 %

Procedure:
The title compound was prepared similarly to Example 1 from 4-isopropylphenacyl chloride and pyridine in a yield of 93%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:13])=[CH:14][CH:15]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(COc2cccc(Br)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3cccc(Br)c3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 4-((3-bromophenoxy)methyl)benzoic acid (0.1 g, 0.32 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (147 mg, 0.76 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (104 mg, 0.77 mmol) and triethylamine (77 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.4 mmol) was added and the resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water (20 mL). The organic phase was separated and concentrated to give a residue. The residue was purified through column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 4-((3-bromophenoxy)methyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (80 mg, 57%). LRMS (M+H+) m/z: calcd 440.07. found 440.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].I[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2ccc(O)cc2)cc1
Reaction time: 0.5 h

Procedure:
50 g of 4-ethynyltoluene, 94.6 g of 4-iodophenol and 250 ml of triethylamine were mixed at RT under a nitrogen atmosphere, and 0.35 g of triphenylphosphine and 0.2 g of copper iodide were added. 0.25 g of bis(triphenylphosphine)palladium(II) chloride were then introduced with stirring. After 30 minutes, a further 0.25 g of bis(triphenylphosphine)palladium(II) chloride and after a further 15 minutes a further 0.25 g of bis(triphenylphosphine)palladium(II) chloride were introduced, during which the temperature was held at between 40 and 55° C. After the reaction mixture had been stirred overnight, it was poured into conc. HCl/ice and subjected to conventional work-up, giving 4-p-tolylethynylphenol in the form of a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11](O)=[O:12])=[O:8])=[O:4].C(OC(Cl)=O)C(C)C.C([N:28](CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([CH2:5][CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH2:28])=[O:12])=[O:8])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
1-(3-Methoxycarbonyl-2-methylpropanoyl)-L-proline (2.4 g.) is dissolved in a mixture of dichloromethane (50 ml.) and triethylamine (1.4 ml.). The solution is chilled in an ice water bath and isobutylchloroformate (1.36 g.) is added while the mixture is stirred. After 10 minutes ammonia (gas) is bubbled through the solution, still in the ice bath, for 15 minutes. The reaction mixture is stirred for 1 hour at room temperature, diluted with methylene chloride (100 ml.) and washed with water, 0.1 N hydrochloric acid, water, and dried over magnesium sulfate. The solvent is removed in vacuo to yield 1-(3-methoxycarbonyl-2-methylpropanoyl)-L-prolineamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:4][CH:3]=1.CC1C=CC=C(SC2SC(=O)NC2=O)C=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[C:39][CH2:40]Br)=[CH:34][CH:33]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[C:39][CH2:40][C:9]2([S:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:34][CH:33]=1
Reactant: Clc1ccc(C#CCBr)cc1
Reactant: O=C1NC(=O)C(Sc2ccc(F)cc2)S1
Agent: Cc1cccc(SC2SC(=O)NC2=O)c1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2ccc(Cl)cc2)(Sc2ccc(F)cc2)S1

Procedure:
Prepared from 5-(4-fluorophenyl-sulfanyl)-thiazolidine-2,4-dione of formula (III), Example 5 and [3-(4-chlorophenyl)-prop-2-ynyl]-bromide of formula (IX), from Example 21: mp 116°-117° C.; Anal. Calc. for C18H11ClFNO2S2 : C, 55.17; H, 2.83; N, 3.57; Found: C, 54.58; H, 2.65; N, 3.39.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](O)=O.C(C1C=CC2C(=CC=CC=2)C=1C(O)=O)=O>>[CH3:11][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:14])[CH:1]=2)[CH:6]=1
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: O=Cc1ccc2ccccc2c1C(=O)O
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
Crystals of a crude 2,6-naphthalenedicarboxylic acid (the content of formylnaphthoic acid: 2,500 ppm; OD400: 1.5; the average particle diameter of the crystals: 5 μm) which was obtained by oxidation of 2,6-dimethylnaphthalene in the liquid phase in the presence of a Co/Mn/Br-based catalyst was mixed with water to prepare a slurry having a concentration of 20% by weight, and 300 g of the obtained slurry was placed into a 500 ml autoclave equipped with a stirrer under an atmosphere of nitrogen and heated at 280° C. Then, crystals of a crude 2,6-naphthalenedicarboxylic acid similar to the material used above was mixed with water to prepare a slurry having a concentration of 20% by weight, and the prepared slurry was supplied continuously into the autoclave at a rate of 120 g/hour at the room temperature. The residence time in the aging tank at 280° C. was kept at 3 hours, and a slurry was continuously taken out of the bottom portion of the autoclave at a rate of 120 g/hour. The crystals of 2,6-naphthalenedicarboxylic acid taken out of the bottom portion of the autoclave had an average particle diameter of 50 μm. The solubility of 2,6-naphthalenedicarboxylic acid in water at 280° C. is about 6 g in 100 g of water.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.C(N(CC)C(C)C)(C)C.F[C:28]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:29]=1[C:30]#[N:31]>O1CCCC1>[C:30]([C:29]1[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:28]=1[N:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH:3]1[C:7]([O:9][CH3:10])=[O:8])#[N:31]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cc1C#N

Procedure:
To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (80 g, 328 mmol) and N,N-diisopropylethylamine (192 mL, 741 mmol) in 300 mL of dry tetrahydrofuran was added 2-fluoro-5-nitrobenzonitrile (36 g, 219 mmol) at room temperature. The reaction mixture was heated to reflux for 36 hours. The reaction was concentrated and the resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to give the title compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 3.01-3.15 (m, 1H), 3.29-3.36 (m, 1H), 3.34-3.36 (m, 1H), 3.48-3.55 (m, 1H), 3.66 (s, 3H), 3.72-3.76 (m, 1H), 4.43-7.48 (m, 1H), 4.96-4.98 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 8.32 (dd, J=9.5, 2.8 Hz, 1H), 8.55 (d, J=2.8 Hz, 1H); MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:37](Cl)(=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][O:8][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
In 4 ml of methylene chloride was dissolved 208 mg of 17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method as described in Example 6. To this solution was added 0.5 ml of pyridine, and the mixture was ice-cooled. To the mixture was added slowly a solution of 241 mg of valeryl chloride in 2 ml of methylene chloride, and the mixture was stirred for one hour. To this reaction liquid was added 60 ml of ethyl acetate, and the mixture was washed successively with 30 ml of water, 10 ml of a dilute aqueous solution of sodium carbonate, 30 ml of water, 5 ml of dilute hydrochloric acid and twice 30 ml of water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the resultant residue was subjected to preparative thin layer chromatography (silica gel) for purification whereby 186 mg (yield: 87.4%) of the title compound was obtained as colorless needle crystals (recrystallized from ether-hexane). Shown below are physical properties and various analytical data of this compound.