Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[Cl:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[C:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH:5]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 29.1 %

Procedure:
A mixture of 4-(4-methoxy-phenoxy)-3,5-dichloro-nitrobenzene (1 g, 3.4 mmol), p-fluorophenylsulfonyl chloride (1.33 g, 6.8 mmol) and Eaton's reagent (20 mL) was stirred at 110° C. for 4.5 h and the solution turned brown. The brown solution was poured into ice water and extracted with EtOAc (3×30 mL). The combined extracts were washed with sat'd sodium bicarbonate (3×50 mL), brine (50 mL), dried and concentrated. The residue was purified by chromatography (20% EtOAc in Hexanes) to give the title compound of Step A (468 mg). MS (APCl−) Calc.: 471.0, Found: 470.0 (M−1).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:13]2=[O:32])[CH:6]=1)[NH2:4].[C:33](Cl)(=O)[CH3:34]>N1C=CC=CC=1>[CH3:33][C:34]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=2)[CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:13]2=[O:32])[N:4]=1
Reactant: CC(=O)Cl
Reactant: NC(=NO)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: c1ccncc1
Product: Cc1nc(-c2cccc(CN3C(=O)C4(COc5cc6c(cc54)CCO6)c4ccccc43)c2)no1
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of N′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide (0.36 g, 0.84 mmol) in pyridine (3 mL) was added acetyl chloride (0.12 mL, 1.68 mmol). The reaction was stirred in a microwave reactor (170° C., 200 watts, 200 psi) for 30 min. The mixture was concentrated in vacuo. The residue was purified by column chromatography with ethyl acetate in hexanes (25% to 40% gradient), and recrystallized from ethyl acetate and diethylether to afford 1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.27 g, 71%) as a colorless solid: mp 209-213° C.; 1H NMR (300 MHz, CDCl3) δ8.06-8.03 (m, 1H), 7.99-7.96 (m, 1H), 7.48-7.44 (m, 2H), 7.19-7.12 (m, 2H), 7.03-6.98 (m, 1H), 6.77-6.74 (m, 1H), 6.58 (s, 1H), 6.42 (s, 1H), 5.18 (d, J=15.8 Hz, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.85 (d, J=15.8 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.56-4.50 (m, 2H), 3.07-2.95 (m, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.0, 176.7, 168.1, 161.9, 161.3, 141.9, 136.6, 132.8, 129.9, 129.6, 128.8, 127.5, 126.9, 126.0, 124.0, 123.6, 120.2, 120.1, 119.1, 109.2, 93.2, 80.6, 72.4, 57.8, 43.8, 29.1, 12.4; MS (ES+) m/z 451.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:32]=[CH:31][C:21]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[C:20]([O:33][CH3:34])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:32]=[CH:31][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[C:20]([O:33][CH3:34])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)O
Yield: 88 %

Procedure:
A solution of tert-butyl 2-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)acetate Example 14 (370 mg; 0.741 mmol) in 1:1 TFA/CH2Cl2 (6 mL) was stirred at rt for 1 h. After concentration under reduced pressure and azeotroping with toluene, the residue was triturated with MeOH to afford the title compound (290 mg; 88%) as a white solid. 1H NMR (DMSO-d6) δ 3.79 (s, 3H), 4.75 (s, 2H), 6.99-7.04 (m, 2H), 7.22 (d, J=2.20 Hz, 1H), 7.57 (d, J=8.80 Hz, 2H), 7.91 (d, J=8.25 Hz, 2H), 7.97 (s, 1H), 8.40 (s, 1H), 13.06 (s, 1H); 13C NMR (DMSO-d6) δ 55.76, 64.86, 111.95, 112.70, 119.41, 121.70, 121.98, 127.83, 129.26, 130.21, 131.18, 134.26, 147.36, 148.80, 149.44, 149.79, 156.06, 157.39, 169.9; HPLC (Method #1): 3.44 min retention time; MS (ES): m/z 443 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:19])(=O)=O.C(O)(=O)C>O>[CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH2:14][Cl:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCON=C(C(=O)CCl)C(=O)OCC
Yield: 92 %

Procedure:
A solution of ethyl 2-n-butoxyimino-3-oxobutyrate (syn isomer, 48.8 g.), sulfuryl chloride (31.5 g.) and acetic acid (48.8 ml.) was stirred at 40° C. for 10 minutes and further at room temperature for 5.5 hours. After water (300 ml.) was added to the resultant solution under ice cooling, the solution was extracted with methylene chloride three times. The extract was washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo to give ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]1
Reactant: N[C@H]1CC[C@H](CO)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CO)CC1)C1CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (1.16 g, 3.75 mmol) was reacted with (trans-4-aminocyclohexyl)methanol (726 mg, 5.61 mmol) to afford the desired product (1.23 g, 81%) as a white solid. ESI MS m/z 403 [C20H23BrN2O2+H]+
Reaction SMILES: CCN(CC)CC.Cl[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:17]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][CH2:18]1.O>CCOC(C)=O>[N:17]1([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: C1CCC2NCCCC2C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)N1CCCC2CCCCC21

Procedure:
3.38 mL of Et3N and 1.44 mL (11 mmol) of ethyl 3-chloro-3-oxopropionate are added to a solution of 1.5 mL (10 mmol) of decahydroquinoline in 100 mL of AcOEt. The resulting solution is kept under stirring at reflux for 10 h. Then water is added and the organic phase is separated, the aqueous phase is extracted once again with AcOEt. The organic phases are pooled and they are first washed with 5% solution of NaHCO3 and subsequently with brine, they are dried over anhydrous
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35].[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C:44](=[O:51])[CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1>C1COCC1>[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[CH:34]([CH3:35])[C:44]([C:38]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=1[F:36])([OH:51])[CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCc1ccncc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1ccncc1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -20 °C

Procedure:
To a solution of diisopropylamine (1.01 g, 10 mmol) in dry THF (60 ml) at -60° C. and under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane (6.25 ml, 10 mmol). The mixture was allowed to warm to -20° C. them recooled to -70° C. and to the resulting solution of lithium diisopropylamide (LDA) (10 mmol) at -70° C. was added dropwise 3-chloro-4ethylpyridine (see D. L. Comins et al, Heterocycles, 22, 339(1984)) (1.41 g, 10 mmol). The resulting mixture was stirred at this temperature for 15 minutes after which time a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.23 g, 10 mmol) in THF (15 ml) was added. This mixture was allowed to warm to room temperature over a 30 minute period and the reaction was quenched by the addition of water (30 ml) and extracted with ethyl acetate (3×60 ml). The combined organic extracts were dried over magnesium sulphate, filtered, concentrated under reduced pressure and the title compound isolated by "flash " chromatography on silica eluting with ethyl acetate. The product was recrystallised from ethyl acetate (yield=0.46 g), m.p. 182°-184° C. Found: C,55.76; H,4.15; N,15.23; C17H15ClF2N4O requires: C,55.98; H,4.14; N,15.36%.
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5](=[O:21])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]([F:19])=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:12]=1>C1COCC1>[F:19][C:10]1[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]([O-:21])=[O:4])=[N:12][C:11]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[Na+:2]
Reactant: COC(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.43 ml of 2N sodium hydroxide is added to a solution of 116 mg of (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid methyl ester in 1.2 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5, so as to give 110 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate, the characteristics of which are the following:
Reaction SMILES: C(OC([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H](C3C=CC=CC=3)C)[CH2:14][C@H:13]2[F:25])[CH2:11][CH2:10]1)=O)(C)(C)C.[NH2:26][C:27]1[C:40]2[C:39](=[O:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:32]3[C@@H:33]([CH3:36])[CH2:34][O:35][C:30]([C:31]=23)=[C:29](F)[C:28]=1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd].CS(C)=O>[NH2:26][C:27]1[C:40]2[C:39](=[O:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:32]3[C@@H:33]([CH3:36])[CH2:34][O:35][C:30]([C:31]=23)=[C:29]([N:15]2[CH2:16][C@H:12]([C:9]3([NH2:8])[CH2:11][CH2:10]3)[C@H:13]([F:25])[CH2:14]2)[C:28]=1[F:46]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](F)[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H]1COc2c(N3C[C@@H](F)[C@@H](C4(N)CC4)C3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reaction time: 4 h
Yield: 76.1 %

Procedure:
4-(R)-(1-tert-Butoxycarbonylaminocyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]pyrrolidine (900 mg, 2.58 mmol) was dissolved in ethanol (20 ml). After adding a 10% palladium-carbon catalyst (moisture content: 50.2%, 900 mg), the mixture was stirred under a hydrogen atmosphere for 4 hours. After filtering off the catalyst through celite (washed with ethanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (20 ml) and 8-amino-9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (593 mg, 2.00 mmol) and triethylamine (3 ml) were added thereto. Then the mixture was stirred in a nitrogen atmosphere in an oil bath at 100° C. for 25 hours. After allowing it to cool, dimethyl sulfoxide was evaporated under reduced pressure and the residue was dissolved in chloroform (100 ml.) and washed with a 10% aqueous solution of citric acid (80 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. Under ice cooling, concentrated hydrochloric acid (10 ml) was dropped into the residue followed by stirring at room temperature for 30 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×4) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide. The pH value of this aqueous solution was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (500 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol and dried under reduced pressure to obtain 640 mg (76.0%) of the title compound as a yellow powder.
Reaction SMILES: [Cl-].[Na+].CC([O:6][CH2:7][C:8]([C@@H:10]1[C@@:14]2([CH:30]=[O:31])[CH2:15][C@H:16]([OH:29])[C@@H:17]3[C@:27]4([CH3:28])[C:21](=[CH:22][C:23]([CH2:25][CH2:26]4)=[O:24])[CH2:20][CH2:19][C@H:18]3[C@@H:13]2[CH2:12][CH2:11]1)=[O:9])=O.[Na].[K]>O.O.O>[CH3:28][C@@:27]12[C@H:17]3[C@@H:16]([OH:29])[CH2:15][C@:14]4([CH:30]=[O:31])[C@@H:10]([C:8]([CH2:7][OH:6])=[O:9])[CH2:11][CH2:12][C@H:13]4[C@@H:18]3[CH2:19][CH2:20][C:21]1=[CH:22][C:23](=[O:24])[CH2:25][CH2:26]2
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]12C=O
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C=O)[C@@H](C(=O)CO)CC[C@@H]12
Reaction time: 16 h

Procedure:
Male rats of the Sprague-Dawley strain weighing about 180 g were surrenalectomized and at that moment, the rats received with their drinking water physiological serum. On the 4th day, the animals were fasted for 16 hours and then received as drinking water water containing 5% glucose. The test product was administered orally at the end of 16 hours in the form of a suspension in 0.25% carboxymethylcellulose. One hour after the administration of the product, they received intraperitoneally a surcharge of aqueous sodium chloride at a rate of 5 ml per 100 g of body weight of 9% physiological serum and subcutaneously 1 μg/kg of an alcoholic solution of 2.5% of aldosterone acetate. The animals were placed in diuresis cages without food or drink for 4 hours. At the end of this time, a miction was forced by pressure on the bladder and the volume of urine was adjusted to 50 ml and the amount of sodium and potassium was determined with an autoanalyser. The results expressed as the percentage of inhibition of the activity of 1 μg/kg of aldosterone monoacetate injected subcutaneously with the ratio of ##EQU1## in the surrenalectomized rats is reported in the following Table.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:5]([O:8][CH2:9][O:10][CH3:11])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[SH:67][CH2:68][CH2:69][C:70]([O:72][CH3:73])=[O:71]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][O:14][CH2:13][O:12][C:4]1[CH:3]=[C:2]([S:67][CH2:68][CH2:69][C:70]([O:72][CH3:73])=[O:71])[CH:7]=[N:6][C:5]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COC(=O)CCS
Reactant: COCOc1cc(Br)cnc1OCOC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(SCCC(=O)OC)cnc1OCOC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A solution of 5-bromo-2,3-bis(methoxymethoxy)pyridine (Intermediate 41; 2 g, 7.19 mmol) in dioxane 40.0 ml) was degassed and to this was added DIPEA (2.51 ml, 14.38 mmol), Xantphos (0.333 g, 0.575 mmol) and Pd2(dba)3 (0.263 g, 0.288 mmol). Methyl 3-mercaptopropanoate (0.951 g, 7.91 mmol) was then added as a solution in dioxane (4 mL) and the reaction was heated under reflux for 1 hour before being cooled to room temperature and filtered through a pad of celite, washing with ethyl acetate. The combined organics were washed with water and then brine, dried (MgSO4) and then concentrated in vacuo. The crude product was purified by column chromatography (SiO2; 0-50% ethyl acetate/petrol) to yield methyl 3-{[5,6-bis(methoxymethoxy)pyridin-3-yl]sulfanyl}propanoate (1.65 g, 72%).
Reaction SMILES: C1OCOC1CO.C(N(CC)CC)C.C12CC(C=C1)CC2C(Cl)=O.[CH:25]12[CH2:31][CH:28]([CH:29]=[CH:30]1)[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH:36]1[CH2:40][O:39][CH2:38][O:37]1)=[O:33]>O.C1(C)C=CC=CC=1>[CH:25]12[CH2:31][CH:28]([CH2:29][CH2:30]1)[CH:27]=[C:26]2[C:32]([O:34][CH:35]1[CH2:36][O:37][CH2:38][O:39][CH2:40]1)=[O:33]
Reactant: O=C(OCC1COCO1)C1CC2C=CC1C2
Agent: O=C(Cl)C1CC2C=CC1C2
Agent: OCC1COCO1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OC1COCOC1)C1=CC2CCC1C2
Reaction time: 5 h
Yield: 95 %

Procedure:
To a mixture of 104 g of glycerol formal, 111 g of triethylamine and 300 ml of toluene, 157 g of 5-norbornene-2-carbonyl chloride was added over one hour at 20° C. After 5 hours of stirring, 200 ml of water was added to stop the reaction and the mixture was allowed to separate. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 213 g of a mixture of (1,3-dioxolan-4-yl)methyl 5-norbornene-2-carboxylate and 1,3-dioxan-5-yl 5-norbornene-2-carboxylate (boiling point 111-115° C./530 Pa, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1.C(N(CC)CC)C>CC(O)C.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: Clc1ccncn1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(c3ccncn3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 41.9 %

Procedure:
A solution of the compound of Example 77 (200 mg, 0.42 mmol), 4-chloropyrimidine (58 mg, 0.51 mmol) and triethylamine (0.12 mL, 0.85 mmol) in 2-propanol (4.0 mL) was heated under reflux for 23 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with a mixed solvent of ethyl acetate-methanol. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=0/100-5/95) and recrystallized from THF to give the title compound (97 mg, 42%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:11]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Product: Oc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
0.005 mol of 4-aminoresorcinol hydrochloride were dissolved in 7.5 ml of benzoyl chloride, while heating, and the solution was then boiled under reflux for 7 hours. The excess benzoyl chloride was subsequently distilled off in vacuo, 10 ml of ethanol were added to the residue and the mixture was boiled up briefly and, after cooling, rendered alkaline with 10 M NaOH solution. The alkaline solution was introduced into 200 ml of water and brought to pH 3 with concentrated hydrochloric acid, using a pH-meter. The crystal mass which precipitated here was filtered off with suction and recrystallized from 15 ml of toluene. The dried product (250 mg) was uniform according to thin layer chromatography (silica gel plate, ethyl acetate/glacial acetic acid 24:1).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1.[SH:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(OCC)(=O)C>CN(C)C=O>[F:16][C:12]1[CH:11]=[C:10]([CH2:9][S:17][C:18]2[C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=[CH:25][N:26]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=C(O)c1cccnc1S
Reactant: Fc1cc(CCl)ccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1SCc1ccnc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
A solution of triethylamine (7.0 mL, 50 mmol) in N,N-dimethylformamide (20 mL) was added to a solution of 4-chloromethyl-2-fluoropyridine (Reference compound No. 1-1, 5.5 g, 38 mmol) and 2-mercaptonicotinic acid (6.2 g, 40 mmol) in N,N-dimethylformamide (40 mL) under ice-cooling, then the mixture was stirred for 12 hours at room temperature. Ethyl acetate (50 mL) was added to the reaction mixture, the whole was extracted with 0.1 N aqueous sodium hydroxide solution (100 mL). 1 N hydrochloric acid was added to the aqueous layer to adjust to pH 5, and the precipitated crystal was filtered off. The crystal was dried at 80° C. under reduced pressure to give 5.3 g of the title reference compound as a brown solid. (Yield 53%)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=1.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C.Cl>[F:31][C:32]([F:40])([F:41])[C:33]1[CH:34]=[CH:35][C:36]([NH:37][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([N:7]3[C:3]([C:2]([F:1])([F:18])[F:17])=[CH:4][CH:5]=[N:6]3)=[CH:16][CH:15]=2)=[CH:38][CH:39]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-n2nccc2C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
The product from Example 37A (69.8 mg, 0.272 mmol) and DMF (1 drop) in CH2Cl2 (2 mL) was treated with (COCl)2 (29 mL, 0.33 mmol). After stirring for 5 hours, the mixture was concentrated and the residue dissolved in CH2Cl2 (2 mL). The mixture was treated with DMAP (35.8 mg, 0.29 mmol), pyridine (22 mL, 0.27 mmol), and 4-trifluoromethylaniline (41 mL, 0.33 mmol). The mixture was heated at 60° C. for 15 hours, allowed to cool to room temperature, diluted with 1N HCl (4 mL), extracted with CH2Cl2 (2×4 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (15% ethyl acetate in hexanes) to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 2H), 7.93 (br s, 1H), 7.80 (d, 2H), 7.77 (m, 1H), 7.68 (d, 2H), 7.66(d, 2H), 6.88 (m, 1H); MS (m/z) 400, 417.