Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH:14]=[O:15])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:13])[CH:14]=[O:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Temperature: 110 °C
Yield: 88.9 %

Procedure:
1420 g of 1-(p-tert.butylphenyl)-2-formyl-1-propene, prepared as described in paragraph (e), are mixed together with 6 g of 5% palladium/carbon and 6.8 g of soda in 20 ml of water at 70°-75° C. in a stirring autoclave. The autoclave is charged with hydrogen (8 atmospheres) and heated to 110° C. About 230 liters of hydrogen are absorbed after 12 hours. The crude 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde is treated with ether, washed neutral with water and dried over sodium sulphate. After removing the ether, the product is fractionally distilled in vacuo. After separating a first running and a last running, there are obtained 1275 g of 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde in 95% purity (about 88% of theory). Boiling point: 150°-152° C./15 mmHg; nD20 =1.5050.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH3:5])#[C-:2].[F:16][C:17]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:4]([C:3]1[N:1]=[CH:2][O:20][C:19]=1[C:18]1[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:17]=1[F:16])[CH3:5]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: [C-]#[N+]C(CC)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ncoc1-c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A mixture of 1-(1-isocyanopropylsulfonyl)-4-methylbenzene (1.55 g, 6.94 mmol), 2-fluoro-4-(trifluoromethyl)benzaldehyde (0.95 mL, 6.9 mmol), and K2CO3 (1.15 g, 8.33 mmol) in MeOH (35 mL) was heated at reflux overnight. The reaction was cooled to ambient temperature and the volatiles evaporated at reduced pressure. The residue was diluted with water and the product extracted with EtOAc. The combined organic extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® 40×150 column, 10%-70% EtOAc/hexanes) to yield 0.89 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.67-7.60 (m, 1H), 7.53-7.48 (m, 1H), 7.47-7.42 (m, 1H), 2.67 (qd, J=7.5, 1.6, 2H), 1.29 (t, J=7.5, 3H). MS (DCI+) m/z 260 (M+H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-n2cccn2)cc1
Temperature: 130 °C
Yield: 18006.2 %

Procedure:
A mixture of methyl 4-fluorobenzoate (2 g, 0.0130 mol), pyrazole (1.33 g, 0.0195 mmol) and potassium carbonate (3.59 g, 0.0260 mol) in dry 1-methyl-1-pyrrolidinone (20 mL) was heated to 130° C. for 44 hours. The cooled reaction mixture was then partitioned between ethyl acetate (200 mL) and 2 M sodium hydroxide (200 mL). The organic phase was separated, washed with 2 M sodium hydroxide (200 mL), 2 M hydrochloric acid (2×200 mL), water (200 mL), and brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white solid (0.71 g). Recrystallization from hexane (40 mL) gave the title compound (0.533 g, 20%) as a white crystalline solid, m.p. 115° C.
Reaction SMILES: [O-2].[Zn+2:2].[CH2:3]([C:17]([OH:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:3]([C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Zn+2:2].[CH2:3]([C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCCC(=O)[O-]
Temperature: 90 °C

Procedure:
Zinc oxide (0.08 g, 1 mmol) and tetradecylcarboxylic acid (0.500 g) were reacted at 220° C for 10 min, cooled to 90° C., then a zinc tetradecylcarboxylate (precursor) was formed. Into said system, toluene (10 ml), trioctylphosphine oxide (3.866 g) and trioctylphosphine (3.7 g) were added. Then a 0.05M aqueous solution of sodium hydrogen selenide (10 ml) was added. After the system was reacted at 90° C. for 3 h, a clear yellow sol containing the ZnSe nanoparticles was obtained. Said sol has a typical exciton absorption peak of the ZnSe nanoparticles, can result in a quantum size effect and emit a fairly strong blue light under the irradiation of a UV lamp.
Reaction SMILES: [CH3:1][CH:2]([NH:4]CCC1C=CC(O)=CC=1)[CH3:3].Br[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(N)(C)C>>[CH3:1][CH:2]([NH:4][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH3:3]
Reactant: CC(C)NCCc1ccc(O)cc1
Reactant: Oc1ccc(CCCBr)cc1
Solvent: CC(C)N
Product: CC(C)NCCCc1ccc(O)cc1
Yield: 97.9 %

Procedure:
Under the conditions outlined above for the preparation of 4-[2-(1-methylethyl)aminoethyl]phenol, 4-(3-bromopropyl)phenol was reacted with isopropylamine. The crude product was distilled in a Kugelrohr apparatus (150°; 1 mm) and the distillate was crystallized from ether to give 4-[3-(1-methylethyl)aminopropyl]phenol (97.9% pure by gas chromatography).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C@@H:19]2[OH:29])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:29][C@H:19]1[C@H:18]2[CH2:30][C@H:17]2[C@H:16]2[C@H:15]3[C@H:24]([CH2:23][CH2:22][C@:20]12[CH3:21])[C@:25]1([CH3:28])[C:12]([CH2:11][C@@H:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26]1)=[CH:13][CH2:14]3)(=[O:33])[CH3:32]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@@]43C)[C@@H]1[C@@H]1C[C@@H]1[C@@H]2O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
6.5 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17β-ol, 13 ml of acetic anhydride, and 26 ml of pyridine were heated for 1.5 hours to 95° C. After ice water precipitation, the sediment was filtered off and taken up in methylene chloride. The solution was washed with water, dried, and evaporated, thus obtaining 6.9 g of crude 17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androstene, used without further purification in the next stage.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:49]=[CH:50][CH:51]=1)[CH2:10][C@@H:11]1[NH:36][C:35](=[O:37])[C@H:34]([CH:38]([CH3:40])[CH3:39])[NH:33][C:32](=[O:41])[CH2:31][C@H:30]([O:42][CH3:43])[CH2:29][CH2:28][CH:27]=[CH:26][C:25]2=[CH:44][C:21](=[CH:22][CH:23]=[CH:24]2)[C@@H:20]([CH3:45])[O:19][C:18](=[O:46])[C@H:17]2[NH:47][N:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1=[O:48])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:6][C:7]1[CH:8]=[C:9]([CH:49]=[CH:50][CH:51]=1)[CH2:10][C@@H:11]1[NH:36][C:35](=[O:37])[C@H:34]([CH:38]([CH3:39])[CH3:40])[NH:33][C:32](=[O:41])[CH2:31][C@H:30]([O:42][CH3:43])[CH2:29][CH2:28][CH:27]=[CH:26][C:25]2=[CH:44][C:21](=[CH:22][CH:23]=[CH:24]2)[C@@H:20]([CH3:45])[O:19][C:18](=[O:46])[C@H:17]2[NH:47][N:13]([CH2:14][CH2:15][CH2:16]2)[C:12]1=[O:48]
Reactant: CO[C@@H]1CCC=Cc2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CO[C@@H]1CC/C=C/c2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)C1
Agent: CO[C@@H]1CC/C=C/c2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)C1
Solvent: C1CCOC1
Product: CO[C@@H]1CCC=Cc2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (E)-(2R,5S,11S,14S,18R)-11-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-14-isopropyl-18-methoxy-2-methyl-3-oxa-9,12,15,28-tetraaza-tricyclo[21.3.1.1*5,9*]octacosa-1(26),21,23(27),24-tetraene-4,10,13,16-tetraone (54 mg, 0.072 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled over an ice bath before addition of tetra-N-butylammonium fluoride (1 M, 108 μL, 0.108 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and then saturated aqueous sodium bicarbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate (3×15 mL). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a brown gum (56 mg). The gum was purified by silica gel chromatography using ethyl acetate/iso-hexanes 3:1 to give a colourless gum (23 mg) which crystallised on standing. The solid was further purified by preparative thin layer chromatography on silica plates using ethyl acetate to yield the title compound (12 mg, 26%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ0.97 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H), 1.63 (d, J=6.5 Hz, 3H), 1.66-1.82 (m, 5H), 1.85-2.04 (m, 3H), 2.16-2.35 (m, 1H), 2.53-2.73 (m, 3H), 2.88 (d, J=6.0 Hz, 2H), 3.43 (s, 3H), 3.47-3.60 (m, 3H), 4.24-4.33 (m, 1H), 4.56 (d, J=11.6 Hz, 1H), 5.59-5.70 (m, 1H), 5.79-5.95 (m, 2H), 5.98-6.12 (m, 1H), 6.69-6.85 (m, 3H), 6.97 (s, 1H), 7.02-7.36 (m, 6H), 8.18 (s, 1H). LCMS (m/z) 635.3 [M+H] Tr=5.42 min.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:36])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH3:35])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:36])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH3:35])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCC)c1
Yield: 59 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, ˜8 eq) of sodium hydroxide and methyl 3-[3′-(3-heptyl-1-methylureido)-2-propoxybiphenyl-4-yl]propanoate, prepared in the preceding step, in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 180 mg of 3-[3′-(3-heptyl-1-methylureido)-2-propoxybiphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=79-80° C.). Yield=59% over the two steps b and c.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].C1(C)C(C)=CC=CC=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>O>[CH2:19]([O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4][OH:3])[CH:21]1[O:23][CH2:22]1
Reactant: ClCC1CO1
Reactant: CC(C)(CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(CO)C(=O)OCC1CO1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
96 parts by wt. 50% sodium hydroxide solution (in water) were added dropwise in 1 hour to 118 parts by wt. (1 1 mole) hydroxypivalic acid and 200 ml xylene, the temperature of the reaction mixture being kept at 110° C. The whole was kept at 110° C. for half an hour. After cooling to 50° C., 276 parts by wt. (3 mole) epichlorohydrin and 50 g Dowex were added to the reaction mixture. The temperature of the reaction mixture rose to 105° C. At this temperature the mixture was afterreacted for 1 hour. After cooling to 50° C. the water was removed azeotropically at reduced pressure (200 mbar). The salt formed and the Dowex were filtered off. The residue was washed twice with 20 ml ECH. The entire organic phase (ECH+xylene) was removed by means of rotary film evaporation. Thus 160 parts by wt. hydroxypivalic glycidyl ester were obtained in the form of a light yellow liquid with an epoxide content of 5.6 meq/g and a hydroxy content of 310 mg KOH/g.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[NH:7])[CH2:4][CH2:3]1.Br[C:10](=[CH:13]OC(C)C)[CH:11]=[O:12].C1(N2C(C=O)=CN=C2C)CC1>>[CH3:1][C:2]1([CH3:8])[N:6]2[C:10]([CH:11]=[O:12])=[CH:13][N:7]=[C:5]2[CH2:4][CH2:3]1
Reactant: CC(C)OC=C(Br)C=O
Reactant: CC1(C)CCC(=N)N1
Agent: Cc1ncc(C=O)n1C1CC1
Product: CC1(C)CCc2ncc(C=O)n21

Procedure:
5,5-Dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde was prepared from 5,5-dimethyl-pyrrolidin-2-ylideneamine (Buckley, et al. J. Chem. Soc. 1947, 1507.) and 2-bromo-3-isopropoxy-propenal in the same manner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: C(S)CCCCCCCCCCC.C(Br)(Br)(Br)Br.[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:27]([O:31]CCCC)(=[O:30])[CH:28]=[CH2:29].C(O)(=O)C=C.[NH4+]>O>[CH:19]([CH:29]=[CH:28][C:27]([OH:31])=[O:30])=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CC(=O)OCCCC
Reactant: C=Cc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: C=CC(=O)O
Agent: CCCCCCCCCCCCS
Solvent: O
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 72 °C

Procedure:
5 parts of dodecanethiol and 3 parts of carbon tetrabromide are added to monomer components consisting of 400 parts of styrene, 90 parts of n-butyl acrylate, and 3 parts of acrylic acid, to give a liquid monomer mixture. Thirty parts of the liquid mixture is poured into 700 parts of ion-exchange water and dispersed well, and after addition of an aqueous ammonium persulfide solution, the mixture is heated to a liquid temperature of 72° C. The remaining 463 parts of the liquid monomer mixture is then added dropwise to the mixture above over 5 hours, to give a dispersion of the styrene-acrylic acid copolymer resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([OH:17])=O)[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.[CH3:47][NH:48][CH3:49].O1CCCC1>C1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([N:48]([CH3:49])[CH3:47])=[O:17])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: CNC
Reactant: CC1(C)COc2c(CCC(=O)O)cc(Br)cc21
Agent: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CCc1cc(Br)cc2c1OCC2(C)C
Reaction time: 1 h
Yield: 84 %

Procedure:
A stirred, cooled (−78° C.) solution of 3-(5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-propionic acid (Intermediate 77, 0.7 g, 2.34 mmol) and triphenyl phosphine (0.74 g, 2.81 mmol) in anhydrous benzene (10 mL) and dichloromethane (20 mL) was treated with hexachloroacetone (0.178 mL, 1.17 mmol). After 1 h, a 2M solution of dimethyl amine in tetrahydrofuran (3 mL, 6 mmol) was added. After 1 h, the reaction mixture was evaporated in vacuo to a brown oil which was subjected to flash column chromatography using 40% ethyl acetate in hexane as the eluent to afford the title compound (0.65 g, 84%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH:20]([C:24]([OH:26])=[O:25])[CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[O:12]=[C:6]1[NH:7][C:8]2[N:9]=[CH:10][CH:11]=[C:2]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH:20]([C:24]([OH:26])=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)[C:3]=2[CH:4]=[CH:5]1
Reactant: O=c1ccc2c(Cl)ccnc2[nH]1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1CCc2ccc(Oc3ccnc4[nH]c(=O)ccc34)cc2C1
Temperature: 180 °C
Yield: 70.1 %

Procedure:
A suspension of 5-chloro-1,8-naphthyridin-2(1H)-one (0.050 g, 0.00028 mol), 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.080 g, 0.00042 mol), and cesium carbonate (0.270 g, 0.000829 mol) in DMF (1 mL) was subjected to microwave heating (180° C.) for 15 min. The reaction mixture was dissolved in water and then acidified to pH of 2 with 1N HCl. The mixture was extracted with EtOAc (4×). The combined organic solutions were dried over MgSO4, filtered, and concentrated. The residue was triturated with DCM and hexanes to produce 7-[(7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid as a white solid (0.066 g, 71%). LCMS: (FA) ES+ 337.3.
Reaction SMILES: I.CSC1NCCCN=1.I.CS[C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.NC1[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:21]2[N:22]([C:27](=[O:31])C=1N=O)[CH2:23][CH2:24][CH2:25][N:26]=2>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:20]2[C:15]3[NH:14][CH:13]=[N:17][C:16]=3[C:27](=[O:31])[N:22]3[CH2:23][CH2:24][CH2:25][N:26]=[C:21]23)=[CH:34][CH:35]=1
Reactant: NC1=C(N=O)C(=O)N2CCCN=C2N1Cc1ccc(Cl)cc1
Reactant: CSC1=NCCN1
Agent: CSC1=NCCCN1
Agent: I
Product: O=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCCN12

Procedure:
Procedure 1 is repeated with substitution of 2-(methylthio)-3,4,5,6-tetrahydropyrimidine hydroiodide for the 2-(methylthio)-2-imidazoline hydroiodide specified. The resulting 8-amino-3,4-dihydro-9-[(4-chlorophenyl)methyl]-7-nitroso-2H,5H-pyrimido(1,2-a) pyrimidin-6(9H)-one is converted to the corresponding 7-formylamino compound according to the method of Procedure 2, and the latter is then cyclized to the desired product by the method of Procedure 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][NH2:16])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH2:17](OC(OCC)OCC)C>>[CH3:1][O:2][C:3]1[C:4]2[N:5]([CH:17]=[N:16][N:15]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccc2nc(NN)c(OC)nc2c1
Reactant: CCOC(OCC)OCC
Product: COc1ccc2c(c1)nc(OC)c1nncn12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 1.5 g. (0.068 mole) of 3,6-dimethoxy-2-hydrazinoquinoxaline and 20 ml. of triethylorthoformate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 1.8 g. of pure 4,7-dimethoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 238°-240° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1.ClS([N:24]=[C:25]=[O:26])(=O)=O>C(Cl)Cl>[NH2:24][C:25]([NH:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1)=[O:26]
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(C(N)=O)c(NC(N)=O)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A solution of 2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (1, 71 mg, 0.28 mmol) in DCM (1 mL) was cooled to 0° C. and chlorosulfonyl isocyanate (27 μL, 0.31 mmol) was added. The mixture was stirred at 0° C. under an atmosphere of argon. After 2 h, the reaction was quenched with a few drops of water and concentrated under reduced pressure. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to yield 2-[(aminocarbonyl)amino]-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (21, 15 mg, 18%). NH4OAc standard conditions. DAD Retention time=6.40 min. M+H=298. 1H NMR (300 MHz, DMSO-d6): δ 11.44 (s, 1H), 9.04 (s, 1H), 8.70 (br s, 1H), 8.30 (br s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.49 (t, J=8.1 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.24 (br s, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])(=O)=O.[Li+].[Br-:17]>CN(C=O)C.CCOC(C)=O>[Br:14][C:10]1[CH:9]=[C:8]([F:15])[C:7]([CH2:6][Br:17])=[C:12]([F:13])[CH:11]=1
Reactant: CS(=O)(=O)OCc1c(F)cc(Br)cc1F
Reactant: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(F)c1CBr
Temperature: 90 °C

Procedure:
To a solution of 4-bromo-2,6-difluorobenzyl methanesulfonate (from Step A above) in DMF (400 mL) was added LiBr (28.8 g, 335 mmol) and heated to 90° C. for 45 minutes. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water (5×), brine (2×) dried over MgSO4, and concentrated in vacuo to yield a brown oil. The crude residue was purified via silica gel column chromatography (CH2Cl2/hexanes) to yield the title compound (24 g).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[OH:3].CCN(CC)CC.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Si:13]([O:3][CH:2]([CH3:4])[C:1]#[N:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a flask containing DL-lactonitrile (36.3 mmol, 2.8 g) in DCM (25 ml), Et3N (54.7 mmol, 8.1 ml) and tert-butyldiphenylsilyl chloride (36.3 mmol, 10 g) were added. The resulting solution was stirred at RT for 24 h. The reaction mixture was quenched with H2O and extracted with DCM. The organic layer was washed with brine, dried, filtered and evaporated. The crude product was purified by flash-chromatography. Yield 4.52 g. 1H-NMR (400 MHz; CDCl3): δ 1.10 (s, 9H), 1.50 (d, 3H), 4.43 (q, 1H), 7.39-7.51 (m, 6H), 7.65 (d, 2H), 7.71 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25]([N:29]1[CH2:33][CH2:32][O:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:30][N:29]([CH2:33][CH2:32][OH:31])[CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Reactant: CCCCN1CCOC1
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(CN(CCO)CCCC)c(O)c(OC)c1)O2
Yield: 56.6 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane and 15.5 g of 3-butyl-1,3-oxazolidine are held in 180 ml of absolute alcohol for 36 hours at 70° C. and subsequently the solvent and excess 3-butyl-1,3-oxazolidine are removed in vacuum. After purification by means of a chromatographic column there is obtained 15.8 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenyl-methyl)-N-(2-hydroxyethyl)-N-butylamine, a colourless oil.