Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Br)=[CH:8][C:9]3[C:23](=[O:24])C4=C5[C:11]6=[C:12]([CH:15]=[C:16](Br)[C:17]5=[CH:18][CH:19]=C4)C(=O)[C:3](=[C:4]2[C:10]=36)[CH:2]=1.C(=O)([O-])[O-:28].[Na+].[Na+].[N:33]([O-])=O.[Na+]>>[C:23]([OH:24])(=[O:28])[CH2:9][CH2:8][CH2:7][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:10][CH2:11][CH2:12][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[NH3:33]
Reactant: O=C([O-])[O-]
Reactant: O=c1c2cc(Br)c3cccc4c(=O)c5cc(Br)c6cccc1c6c5-c2c34
Reactant: O=N[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCC(=O)O
Product: N

Procedure:
A similar tinctorial result is obtained if dyeing is carried out with 0.162% of the dye Vat Orange 3 of C.I. No. 59,300 by the IK process at 40° C. and a falling temperature, instead of the dye mentioned above, and if, instead of sodium carbonate and sodium nitrite, the following chemicals are employed: 9 cm3 /l of 32.5% strength sodium hydroxide solution, 4 g/l of hydrosulfite, concentrated powder (sodium dithionite), and 15 g/l of calcined sodium sulfate, as well as 2 g/l of a 50 percent strength by weight formulation of the condensation product formed from stearic acid and ammonia which has been oxethylated with 5 moles of ethylene oxide.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([NH:15][NH2:16])(=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11].[C:17]1([OH:23])C=CC=CC=1>>[O:11]1[C:17](=[O:23])[NH:13][N:12]=[C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1[O:14][C:1](=[O:2])[NH:16][N:15]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)CCCCC(=O)NN
Reactant: Oc1ccccc1
Product: O=c1[nH]nc(CCCCc2n[nH]c(=O)o2)o1
Temperature: 85 °C

Procedure:
A solution of 200 g of phosgene in 1.6 kg of phenol was introduced at 20° C. into a 4-liter phosgenation apparatus, and 174 g of adipic acid dihydrazide were added thereto. The mixture was heated to 85° C. within one hour, with stirring; gas evolved above a reaction temperature of 45° C. Phosgene was then introduced into the reaction mixture at 85° C. over 5 hours (approx. 30 g per hour), with stirring. The solution was then purged with nitrogen at 85 to 90° C. for 30 minutes, and the major part of the phenol was finally removed by vacuum distillation at from 50 to 60° C. The remaining product was dissolved in 1 liter of toluene at 60° C. and precipitated by cooling to 20° C. The precipitate was suction filtered, washed with toluene and dried under vacuum.
Reaction SMILES: O.[CH2:2](I)I.[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH2:14][OH:15]>CC(O)=O.[Zn]>[CH3:13][C:8]1([CH3:12])[CH2:9][CH2:10][CH2:11][C:6]2([CH3:2])[C:7]1([CH2:14][OH:15])[CH2:5]2
Reactant: CC1=C(CO)C(C)(C)CCC1
Reactant: ICI
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCCC2(C)CC12CO
Temperature: -5 °C
Reaction time: 0.05 h

Procedure:
A solution of 0.4 g of Cu(OAc2).H2O in 20 mL of hot HOAc was treated with 8.8 g (0.13 g-atom) of Zn dust with shaking for 3 min, and the acid was decanted. The Zn-Cu couple was washed by decantation with 30 mL of 1:1 HOAc/Et2O, followed by Et2O (6×30 mL). Next, 20 mL of Et2O was added together with a crystal of I2. A mixture of 18.8 g (70 mmol) of CH2I2 and 3.08 g (20 mmol) of β-cyclogeraniol (l) was added dropwise over a 20-min period, with warming to maintain a gentle reflux. Heating at reflux was continued for an additional 2 h. The cooled solution was decanted, the residue was washed with Et2O, and the total Et2O volume was brought to 200 mL. The solution was cooled in ice/H2O, and pyridine (8 to 9 mL) was added dropwise until no further ZnI2 -pyridine complex separated. The reaction was cooled to -5° C. overnight, filtered twice, and evaporated. Further complex separated on evaporation. TLC (9:1 hexane/EtOAc) demonstrated a single product. The crude oil was eluted through a 3×25 cm silica gel column by 9:1 hexane/Et2O, followed by 1:1 hexane/Et2O. The spectrally pure, colorless oil weighed 3.4 g (quant): IR (film) 3400 (OH), 1460, 1385, 1365, 1155, 1035, 1010, 705 cm-1 ; 1H NMR (CDCl3) δ0.22 (d, J=4.5 Hz, 1, cyclopropyl H), 0.49 (d, J=4.5 Hz, 1, cyclopropyl H), 0.99 (s, 3, CH3), 1.21 (s, 3, CH3), 1.26 (s, 3, CH3), 1.0-1.8 [m, 7, (CH2)3, OH], 3.51 and 3.92 (d, J=12 Hz, 1, and dd, J=12 and 3.5 Hz, 1, CH2O); 13C NMR (CDCl3), 65.8, 38.0, 35.5, 31.9, 31.3, 29.2, 27.4, 23.9, 22.5, 21.7, 18.0 ppm; MS calcd for C11H20O 168.1514, found 168.1521.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CC2)c(O)c1
Temperature: 50 °C
Yield: 53.2 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (0.5 g, 3.62 mmol), K2CO3 (0.550 g, 3.98 mmol) and (bromomethyl)cyclopropane (0.386 ml, 3.98 mmol) in DMF (12 ml) was heated to 50° C. overnight. The reaction mixture was portioned between EtOAc and HCl 1N. The organic phase was washed several times with brine and dried over Na2SO4; the solvent was removed; and the crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=90:10 to 85:15) to give 4-(cyclopropylmethoxy)-3-hydroxybenzaldehyde (0.370 g, 1.925 mmol, 53.2% yield, MS/ESI+ 193.0 [MH]+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[N:36]=[C:37]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)[C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:51]([N:48]1[CH2:47][CH2:46][N:45]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[C:35]([C:18]3[CH:17]=[CH:16][C:15]([S:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:13])=[O:14])=[CH:20][CH:19]=3)[N:36]=2)[CH2:50][CH2:49]1)[CH3:52]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCCOCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 72.7 %

Procedure:
(4-Tributylstannylphenyl) (3-benzyloxypropyl) sulfone (5.78 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (2.13 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.58 g) in xylene in nitrogen atmosphere for 7 hr. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate and adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(3-benzyloxypropyl)sulfonylphenyl]isoquinoline (2.56 g) as a pale brown amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[CH2:6].Cl[P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[C:19]1([P:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[CH3:10])[CH:5]=[CH2:6])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc(C)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C)c(P(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
Mg (0.72 g, 30 mmol) was placed in a 50 mL of round-bottom flask. The flask was dried and filled with nitrogen. Anhydrous THF (10 mL) was injected first and followed by injection of a half amount of a solution of 3-bromo-4-methyl-styrene (3.94 g, 20 mmol) in anhydrous THF (10 mL). After an exothermic reaction started, the second half of the solution was added. The resulting Grignard reagent was added to a solution of chlorodiphenylphosphine (5.25 g, 25 mmol) in anhydrous THF (10 mL) at 0° C. After the addition, the reaction mixture was warmed to the room temperature and stirred for another 20 h. Then, it was poured into a saturated NH4Cl aqueous solution (10 mL) at 0° C. and extracted with anhydrous THF (3×20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated to a volume of 5 mL. Hexane was added into the resulting oil to precipitate by-products. After filtration and concentration, the residue was purified by a flash column chromatography (hexane/EAC=4/1) to afford 2.42 g of the desired product (39% yield). 1H NMR (300 MHz, CDCl3) δ 2.36 (3H, s), 5.06 (1H, d, J=10.9 Hz), 5.42 (1H, d, J=17.6 Hz), 6.48 (1H, q, J=10.9, 17.6 Hz), 6.79 (1H, q, J=2.1, 5.8 Hz), 7.20–7-34 (11H, m); 13C NMR (75 MHz, CDCl3) δ 20.8, 21.1, 113.0, 126.2, 128.5, 128.6, 128.8, 130.2, 130.3, 130.7, 133.9, 134.1, 135.1, 136.0, 136.3, 136.5, 141.7 ppm; 31P NMR (121 MHz, CDCl3) δ−12.34 ppm; IR (neat) 3057 (m), 3016 (s), 2974 (m), 1957 (w), 1900 (w), 1819 (w), 1629 (m), 1589 (m), 1479 (s), 1435 (s), 1380 (m), 1306 (w), 1262 (m), 1179 (m), 1152 (m), 1093 (m), 1028 (m), 992 (m), 911 (s), 830 (s), 699 (s); MS m/z 302 (M+) 223, 183, 165, 152, 115, 78; HRMS calcd for C21H19P 302.1224, found 302.1227.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[CH:11][C:10]=2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:51]=[CH:50][C:44]([O:45][CH2:46][C:47](O)=[O:48])=[CH:43][CH:42]=2)[S:35]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:45][CH2:46][C:47]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]([OH:19])=[CH:11][C:10]=4[C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:4][C:3]=3[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:48])=[CH:50][CH:51]=2)[S:35]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)cc2C(C)(C)C)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)cc2C(C)(C)C)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 99.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2,5-di-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.71 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.68 g), diethyl cyanophosphonate (0.39 g), triethylamine (0.24 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.13 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](I)[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[F:18][C:19](I)([F:21])[F:20].N1C=CC=CC=1>C(OCC)C.C(OCC)(=O)C.[Cu]>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:19]([F:21])([F:20])[F:18])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: FC(F)(F)I
Reactant: COC(=O)c1cccc2c(I)c(OC)ccc12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 120 °C
Yield: 75.1 %

Procedure:
A mixture of 5-iodo-6-methoxy-1-naphthalenecarboxylic acid methyl ester (10.26 g, 30 mmoles, described in Example 1f), trifluoromethyl iodide (12 g, 61.2 mmoles), freshly prepared copper powder (5.7 g, prepared according to the procedure of R. Q. Brewster and T. Groening, "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) and pyridine (45 ml) was charged into a stainless steel autoclave. The vessel was shaken and heated at 120° C. for 20 hr and cooled to room temperature. The mixture was diluted with diethyl ether-ethyl acetate (1:1). The insoluble material was removed by filtration. The filtrate was washed with 1N aqueous HCl, water and dried (MgSO4). The solvent was removed under reduced pressure. The residue was crystallized from ethanol to give 6.4 g of 5-(trifluoromethyl)-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 79°-80° C.; NMR (CDCl3) δ 3.95 (s, 6H), 8.00 (m, 5H). A mixture of the latter ester (6.3 g, 22 mmoles), 1N aqueous NaOH solution (34.12 ml) and methanol (100 ml) was stirred at 20°-22° C. for 4 hr. The mixture was adjusted to pH 7 with 1N aqueous HCl, methanol was removed from the mixture by distillation and the concentrated mixture was made acidic (pH 2) with 1N aqueous HCl. The resulting precipitate was collected and dried to yield 6 g of the title compound; mp 218°-219° C.; NMR (DMSO-d6) δ4.0 (s, 3H), 8.3 (m, 5H), 10.6 (broad, 1H).
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][CH:24]=3)[CH:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][CH:24]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2csc(CO)c2)nc2c(C=O)cnn12)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CO)c3)nc12
Reaction time: 1 h
Yield: 23 %

Procedure:
Tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (20 mg, 0.05 mmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL). After 1 h, the solution was concentrated under a stream of air. The residue was purified via preparative HPLC to furnish 7-(cyclopropylamino)-5-(5-(hydroxymethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 2,2,2-trifluoroacetate (4.8 mg, 23%).
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[Cl:23])(=O)C1C=CC=CC=1.[CH:24]1([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O)CCC.Cl>C(OCC)(=O)C>[ClH:23].[CH:24]1([N:29]([C:19]2[N:18]=[CH:17][N:16]=[C:15]3[C:20]=2[N:21]=[CH:22][N:14]3[CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Reactant: Cc1ccc(C)c(CNC2CCCC2)c1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(CN(c2ncnc3c2ncn3COCCO)C2CCCC2)c1
Yield: 75 %

Procedure:
A mixture of 9.0 g. (27 mmole) 9-[(2-benzoyloxyethoxy)-methyl]-6-chloropurine, 16.5 g. (81 mmole) N-cyclopentyl-(2,5-dimethylbenzyl)-amine and 130 ml. butanol is heated under reflux for 16 hours. The reaction mixture is evaporated, the residue is taken up in dichloromethane, washed with dilute acetic acid and subsequently with water, dried over anhydrous sodium sulphate, evaporated, mixed with a solution of 3.3 g. sodium in 200 ml. methanol, heated under reflux for 3 hours, evaporated and the residue taken up in water, extracted with dichloromethane, dried over anhydrous sodium sulphate and evaporated. After chromatography on silica gel with an elution mixture of 95% dichloromethane and 5% methanol, there are obtained 8.0 g. of the title compound (75% of theory) in the form of an oily base, the hydrochloride of which, prepared in ethyl acetate, melts at 132°-135° C.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]13[C:25]2[C:16](=[CH:17][C:18]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[CH:24]=2)[O:15][CH2:14]1.N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:39]4[O:44][CH2:43][CH2:42][O:41][C:40]=4[CH:45]=3)OC2)C1=O>>[CH3:39][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:45][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:8]1=[O:13]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c1ccc1ncsc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 6′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (37%): mp 156-158° C.; 1H NMR (300 MHz, CDCl3) δ8.77 (s, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.56 (s, 1H), 6.23 (s, 1H), 4.83 (ABq, 2H), 4.23-4.04 (m, 6H), 3.85-3.77 (m, 2H), 3.67-3.61 (m, 2H), 3.52-3.46 (m, 1H), 3.32 (s, 3H); MS (ES+) m/z 455.1 (M+1).
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1C=O.CC[O:21][CH2:22][CH3:23]>C1COCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:16]([CH:22]([OH:21])[CH2:23][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])=[CH:15][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: CCCCCCCCBr
Reactant: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 ml round bottom flask with a Y adapter, condensor, and a 10 ml addition funnel was added 0.38 g (15.63 mmol) of Mg turnings which had been ground with a mortar and pestle. The apparatus was then flushed with argon and flame dried. After allowing the apparatus to cool under arqon, 4 ml of anhydrous diethyl either was added to the Mg. While vigorously stirring the Mg in the ether, 2.52 g (13.05 mmol) of 1-bromooctane in 3 ml of diethyl ether was added dropwise. After 5 drops, the Grignard reaction started and the addition was continued at a rate sufficient to maintain a steady reflux. After addition was complete, 4 ml of dry THF was added to the Grignard reagent and it was stirred at R.T. for an additional 1/2 hour. A warm water bath was then placed under the flask, and refluxing was continued for 15 minutes. Afterwards, the reaction was cooled to 0° C. with an ice bath and 2.00 g (16.81 mmol) of p bromobenzaldehyde in 4 ml of the THF was added. The reaction was stirred at R.T. for 1.5 hrs., whereupon the Grignard was quenched with saturated NH4Cl. The organic layer was washed with H2O and brine, then dried (MgSO4). Rotary evaporation of the solvent under reduced pressure produced 2.96 g of a crude yellow oil. The oil was dissolved in a diethyl ether and loaded onto a silica gel column. Elution with diethyl ether/hexane yielded 2.22 g of the titled product as a yellow oil.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[CH3:23]>>[C:9]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH3:13])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[CH3:23])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: Cc1cc(O)ccc1N
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Product: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)cc2C)c1C

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol) and 4-amino-3-methyl-phenol (123 mg, 1.0 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as a brown solid: MS (ESI) 306 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[CH2:23][NH:22][CH:21]([CH3:24])[CH2:20][CH2:19]1)[CH3:17]>>[CH2:16]([CH:18]1[CH2:23][N:22]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH:21]([CH3:24])[CH2:20][CH2:19]1)[CH3:17]
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CCC1CCC(C)NC1
Product: CCC1CCC(C)N(C(=O)c2cnoc2-c2ccc(C)cc2)C1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 5-ethyl-2-methylpiperidine (7.6 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.5 mg). HRMS calcd for C19H24N2O2: 312.1838, found 312.1841.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][CH:15]=4)[C:6]=3[N:7]=[C:2]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3cccc4ccccc34)c2n1
Reactant: C1CNCCN1
Product: c1ccc2c(CSc3ncnc4c(N5CCOCC5)nc(N5CCNCC5)nc34)cccc2c1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-morpholino-8-(1-naphthylmethyl-thio)-pyrimido [5,4-d]-pyrimidine (m.p.: 206°-209° C.) and piperazine.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+].C(O)(=O)C>C(O)C.O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: CCCn1c(=O)cc(N)n(C)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCn1c(=O)c(N=O)c(N)n(C)c1=O
Temperature: 25 °C
Yield: 50 %

Procedure:
6-Amino-1-methyl-3-propyl-2,4(1H,3H)pyrimidinedione (V. Papesch and E. F. Schroeder, J.Org.Chem. 1951, 16, 1879) (5.53 g, 27.5 mmol) was dissolved in hot 95% ethanol (20 ml)-water (120 ml). Sodium nitrite (2.32 g) and glacial acetic acid (2.4 ml) were added. The resulting mixture was allowed to cool to room temperature. Orange-pink crystals were filtered off and dried at 50° C. under vacuum to give purple crystals of 6-amino-1-methyl-5-nitroso-3-propyl-2,4 (1H,3H)-pyrimidinedione (2.92 g, 80%); mp 250° dec. Analysis for (C8H12N4O3): C,45.28; H,5.70; N,26.40. Found: C,45.12; H,5.74; N,26.34. 5,6-Diamino-1-methyl-3-propyl-2,4(1H,3H)pyrimidinedione was prepared freshly from 6-amino-1-methyl-5-nitroso-3-propyl-2,4(1H,3H)pyrimidinedione by ammonium sulfide reduction using the method of V. Papesch, M. Grove, and E. F. Schroeder (U.S. Pat. No. 2 602 795). This diamine (2.00 g, 10.0 mmol) was condensed with 4-formylcinnamic acid (1.76 g, 10.0 mmol) by the procedure of Example 2 to give the title compound as an ivory powder, after crystallization from N,N-dimethylformamide-water; mp>300° C. Analysis for (C18H18N4O4.1/5 DMF): C,60.54; H,5.30; N,15.94. Found: C,60.52; H,5.22; N,16.03.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([Cl:33])(=[O:32])[CH:29]([CH3:31])[CH3:30]>>[ClH:33].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:3]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: CC(C)C(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: Cl

Procedure:
50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114) and 29.5 mg (0.28 mmol) of isobutyryl chloride are reacted together by general method F. 12.8 mg (19.5% of theory) of the title compound are obtained.