Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>O1CCCC1>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH2:20][C:33]([N:32]([CH3:36])[CH3:31])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
3-Benzyl-7-chloro-2-methylquinazolin-4 (3H)-one (2 g, 1 eq.) was dissolved in tetrahydrofuran (20 ml). The solution was cooled to −78° C. for 15 minutes. Lithium hexamethyl disilazide (LHMDS) was added slowly and the mixture was stirred at −78° C. for 45 minutes. Dimethylcarbamyl chloride was added and the mixture was stirred at −78° C. for 1 h. The reaction was allowed to warm to room temperature and stirred for 3 h. The solvent was evaporated and the resulting solid was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to give 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (1.2 g) as a solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[CH2:26](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[C@@H:27]1[O:29][CH2:28]1>>[O:29]1[CH2:28][C@@H:27]1[CH2:26][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Product: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OC[C@H]4CO4)cc3)CC2)cc1

Procedure:
A target compound was manufactured as in Example 1, using 4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol and (R)-glycidylnosylate as starting raw materials.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([CH2:15][CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:1][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]([CH2:15][CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: NCCCO
Reactant: CCC(Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC(Oc1cccc(CNCCCO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
tert-Butyl 2-(3-formylphenoxy)butyrate (105.1 mg, 0.42 mmol) was dissolved in chloroform (10 ml) at room temperature, and thereto were added 3-amino-1-propanol (0.04 ml, 0.47 mmol), sodium triacetoxyborohydride (134.6 mg, 0.63 mmol) and acetic acid (0.03 ml, 0.51 mmol) in sequential order at the same temperature, and then stirred at room temperature for 24 hours. The reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution and thereafter extracted by chloroform, to obtain an organic layer. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressured. The resultant substance was purified by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained as a colorless oil (43.3 mg, 33.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:14]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.[OH2:19]>C(O)(=O)C>[CH3:1][C:2]1([CH3:18])[CH2:3][CH2:4][C:5]([CH3:17])([CH3:16])[C:6]2[N:7]=[C:8]3[C:13]([CH2:12][CH2:11][CH2:10][C:9]3=[O:19])=[N:14][C:15]1=2
Reactant: O
Reactant: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
8.0 g of 1,2,3,4,6,7,8,9-octahydro-1,1,4,4-tetramethylphenazine was dissolved in 30 ml of acetic acid, followed by the dropwise addition of a solution of 4.9 g of chromic acid anhydride in acetic acid (30 ml)/water (4 ml). The obtained mixture was stirred at 80° C. for 30 minutes, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 20% ethyl acetate/hexane) to give 1.6 g of the title compound as a brown oil.
Reaction SMILES: [C:1]([CH2:5][C:6]([CH2:9][C:10]([F:13])([F:12])[F:11])(Cl)Cl)([F:4])([F:3])[F:2].Cl.[OH:15]S(O)(=O)=O>>[C:1]([CH2:5][C:6]([CH2:9][C:10]([F:13])([F:12])[F:11])=[O:15])([F:4])([F:3])[F:2]
Reactant: FC(F)(F)CC(Cl)(Cl)CC(F)(F)F
Reactant: O=S(=O)(O)O
Agent: Cl
Product: O=C(CC(F)(F)F)CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
A mixture of 20 mL 100% H2SO4, 10.6 g (0.049 mol) HgO; and 12.0 g (0.048 mol) CF3CH2CCl2CH2CF3 was shaken periodically over 45 min, during which time a thick, nearly white paste resulted. An exothermic reaction also occurred after approximately 10 min and subsided after about 0.5 h. The cooled reaction mixture was added to 75 g ice and 25 mL concentrated HCl. The lower liquid phase was separated and the aqueous layer was extracted with 3×35 mL ether. The combined organic extracts (including the original organic layer) were washed with 10 mL water, dried with Na2SO4 and distilled. Five and three tenths g (56% yield) of 97% pure CF3CH2C(O)CH2CF3 were obtained (boiling point 122-123° C.). 1H NMR: 3.4 (q, J=10.2 Hz). 19F NMR: -63.0 (t, J=10.2 Hz) ppm. IR: 1746 (C=O) cmc-1. MS: 194 (3.4), 111 (100), 91 (17.5), 83 (21.8), 69 (11.9).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=2)[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
Potassium carbonate (2.49 g, 18.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (1.47 g, 15.0 mmol) and 5-fluoro-2-nitrobenzotrifluoride (3.14 g, 15.0 mmol) in DMF (20 ml), and the mixture was stirred under heating at 70° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (40 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish solid of 5-methyl-3-(4-nitro-3-trifluoromethylphenyloxy)pyrazole (2.74 g, yield: 63.6%). mp: 96-98° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.34 (s, 3H), 5.77 (s, 1H), 7.40 (dd, J=2.6 and 8.9 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.98 (d, J=8.9 Hz, 1H), 9.20-10.15 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>>[CH3:1][C:2]([CH3:13])([CH2:7][NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)CNS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CNS(C)(=O)=O)C(=O)O

Procedure:
To a solution of methyl 3-amino-2,2-dimethylpropanoate (249 mg, 1.90 mmol) and Et3N (0.80 mL, 5.70 mmol) in 2 mL CH2Cl2 was added methanesulfonyl chloride (0.29 mL, 3.80 mmol). The reaction was stirred for 2 days, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCl3, and chromatographed (1:1 hex:EtOAc) to provide methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate (124 mg, 31%) as a clear oil. 1H NMR (400 MHz, CDCl3), 4.95 (t, 1H, J=6.8 Hz), 3.69 (s, 3H), 3.16 (d, 2H, J=6.8 Hz), 2.95 (s, 3H), 1.24 (s, 6H). Methyl 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoate was hydrolyzed using aqueous NaOH to provide 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoic acid, which was used without further purification. 1H NMR (400 MHz, CDCl3), δ 10.28 (br. s, 1H), 5.56 (br. s, 1H), 3.14 (s, 2H), 2.94 (s, 3H), 1.25 (5, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[O:14]1[CH2:19][CH2:18][CH:17]([C:20](=[S:22])[NH2:21])[CH2:16][CH2:15]1>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:20]([CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[S:22][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: NC(=S)C1CCOCC1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2csc(C3CCOCC3)n2)c1
Yield: 98.2 %

Procedure:
A mixture of 2-bromo-1-(3-nitrophenyl)ethanone (245 mg, 1 mmol) and tetrahydro-2H-pyran-4-carbothioamide (144 mg, 1 mmol) is suspended in absolute ethanol (20 mL) and heated to reflux for 2 h. The solution is then cooled and evaporated to dryness. The crude is dissolved in DCM and washed twice with a solution of saturated sodium bicarbonate and once with water. The organic layer is dried up with sodium sulfate, filtered and evaporated to dryness to yield 285 mg of the title compound (98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:32].C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:14](=[O:16])[CH2:13][CH2:12][C:10]3[O:9][N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:11]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:32]
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Reactant: NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Reaction time: 2 h

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.136 g) and N,N′-carbonyldiimidazole (0.114 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(4-Chloro-3-fluorobenzyl)-4-piperidinamine (0.150 g) was then added and left to stir for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This was triturated with diethyl ether which caused product the to crystallise. After filtration, the product was washed with diethyl ether and dried to N-[1-(4-chloro-3-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide. m.p. 132° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[C:15]1([C:25](OCC)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([C:25]([CH2:13][C:12]#[N:14])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 2.50 M of n-butyllithium in hexane (49.9 mL, 125 mmol) in tetrahydrofuran (49.9 mL) cooled to −78° C. is added acetonitrile (6.52 mL, 125 mmol) drop-wise. The resulting cloudy mixture is stirred for 30 min. Ethyl α-napthoate (8.87 mL, 49.9 mmol) is added drop-wise and the reaction mixture is stirred at −78° C. for 2 hr. The reaction is warmed to room temperature, quenched with acetic acid (50 ml) and partitioned between ethyl acetate and water. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The crude material is purified by column chromatography (eluent: 5-15% CH2Cl2/methanol) to provide 1-naphthoylacetonitrile (6.99 g, yield 72%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=8.7 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.90 (t, J=8.1 Hz, 2H), 7.71-7.64 (m, 1H), 7.57 (dt, J=15.5, 7.2 Hz, 2H), 4.21 (s, 2H).
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].OCC(OC[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Reactant: O=C(CO)OCc1ccccc1
Product: O=C(COS(=O)(=O)C(F)(F)F)OCc1ccccc1

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with HO-CH2COOBn
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=[CH:12][C:3]1=2.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1>>[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:14][CH2:15][N:16]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH2:22][CH2:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:17][CH2:18]3)=[CH:10][CH:11]=[CH:12][C:3]1=2
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCCO2
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4OCCCO5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine hydrochloride (J. Med. Chem. 1988, 31, 1934–1940) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the intermediate compound. MS: APCI: M+1: 453.6 (Exact Mass: 452.55).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10](CN3CCCC3)[CH:9]=[N:8][C:7]=2[N:6]([CH2:20][CH2:21][CH3:22])[C:5]1=[O:23])[CH2:2][CH3:3].[Li]CCCC.[C:29]1(=[O:38])[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32][CH2:31][CH2:30]1>C1COCC1>[OH:37][C:33]12[O:38][C:29]([C:9]3[NH:10][C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:23])[N:6]([CH2:20][CH2:21][CH3:22])[C:7]=4[N:8]=3)([CH2:36][CH2:35][CH2:34]1)[CH2:30][CH2:31][CH2:32]2
Reactant: O=C1CCCC(=O)CCC1
Reactant: CCCn1c(=O)c2c(ncn2CN2CCCC2)n(CCC)c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(O)(CCC3)O4)nc2n(CCC)c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1,3-Dipropyl-7-pyrrolidin-1-ylmethyl-3,7-dihydro-purine-2,6-dione (638 mg) was taken in dry THF (10 ml) at −78° C. nBuLi (0.88 ml, 2.5M in hexane) was added slowly. The reaction mixture turned orange and stirred for 30 min at −78° C. Cyclooctane-1,5-dione (280 mg,) was dissolved in 3 ml of dry THF, added to the reaction mixture. Stirred at −78° C. for 30 min, slowly warmed to rt and stirred overnight. The reaction mixture was quenched with sat NH4Cl and extracted with ethyl acetate (3×50 ml). Combined organic layer was washed with 1N HCl, water, and brine. Dried over anhydrous Na2SO4 and concentrated. The crude product was purified on silica column, eluted with ethyl acetate:hexane (1:1). Mass (ES+ 377)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([CH:19]=[CH:20][C:21](O)=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.Cl>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([CH:19]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)[CH2:20][C:21](=[O:22])[O:5]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Reactant: Oc1cccc(O)c1
Agent: Cl
Product: O=C1CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Yield: 64 %

Procedure:
Condensation of resorcinol with 3-(1-naphthyl)acrylic acid in the presence of hydrochloric acid/hydrogen chloride (method of J.D. Simpson and H. Stephen, J. Chem. Soc. (London) 1936, 1382) gave the desired dihydrocoumarin, m.p. 203.5°-206.5, in 64% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+](N[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][N:32]([CH3:34])[CH3:33])[CH:30]=2)=[CH:19][N:18]=1)([O-])=O>>[CH3:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:17]2[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][N:32]([CH3:33])[CH3:34])[CH:30]=3)=[CH:19][N:18]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)Cc1cncc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Reactant: Cc1cccnc1CCCCN
Product: Cc1cccnc1CCCCNc1ncc(Cc2cncc(CN(C)C)c2)c(=O)[nH]1

Procedure:
Reaction 4-(3-methylpyridyl)butylamine with 2-nitroamino-5-(5-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone gives 2-[4-(3-methylpyridyl)butylamino]-5-(5-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[CH2:22]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH3:18])[C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCC3C1
Reactant: C=Cc1ccccc1C
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2C)C2CCCN(C1)C2

Procedure:
The coupling of 10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (226.0 mg, 0.999 mmol; Example 201) and 2-methylstyrene (209.0 mg, 176.9 mmol, Alfa Aesar) was performed as described in Example 202, except that the material was purified by reverse-phase HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.09-1.17 (m, 1H), 1.29-1.47 (m, 2H), 1.65-1.74 (m, 1H), 1.97 (s, 3H), 2.18-2.24 (m, 1H), 2.42 (s, 3H), 2.60-2.65 (m, 1H), 2.94-3.08 (m, 5H), 3.81 (d, J=16.3 Hz, 1H), 4.05-4.15 (m, 1H), 4.23 (d, J=16.3 Hz, 1H), 4.36-4.45 (m, 1H), 6.78 (d, J=7.1 Hz, 1H), 6.95-7.06 (m, 4H), 7.16-7.18 (m, 1H), 7.27 (d, J=8.1 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=1.[C:29]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[F:12][C:4]1[CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:29])[N:20]=2)=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(=O)[nH]n3)s2)c(F)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1=O
Temperature: 25 °C

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-[(6-oxo-1,6-dihydropyridazin-3-yl)amino]thiophene-3-carboxamide (Example 578 Step 3) (50 mg, 0.123 mmol), K2CO3 (18.70 mg, 0.135 mmol) and iodomethane (8.08 μL, 0.129 mmol) were stirred in DMF (1 mL) at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue twice by silica gel column chromatography (0-10% MeOH—CHCl3) followed by mass-triggered reverse phase HPLC gave the title compound as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:14]=[C:13]([C:15]#[N:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:14]=1)#[N:16]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(cc(C#N)n2Cc2cccc(F)c2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc2c(O)c(C(=O)NCC(=O)O)ncc2n1Cc1cccc(F)c1

Procedure:
Prepared in analogy to that of Example 1(e) from 2-cyano-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:13]>[OH-].[Na+]>[F:1][C:2]1[C:3]([CH3:10])=[C:4](/[CH:5]=[CH:11]/[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(F)cccc1C=O
Reactant: COc1cccc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C(=O)/C=C/c2cccc(F)c2C)c1
Temperature: 21.5 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
To a stirred solution of 3-fluoro-2-methylbenzaldehyde (150 g, 1.2 mol) in IMS (600 mL) was added 3-methoxyacetophenone (163 g, 1.2 mol). NaOH (10% aq, 750 mL) was added over 40 min using a water bath to maintain a temperature between 18-25° C. The mixture was stirred vigorously at room temperature for 15 h and a thick precipitate was formed. The solid was isolated by filtration, broken up with a mortar and pestle, and washed IMS and water. After drying at 45° C. for 48 h, 273 g (84% yield), the desired product (E)-3-(3-fluoro-2-methylphenyl)-1-(3-methoxyphenyl)prop-2-en-1-one was obtained (characterized by LCMS and 1H NMR, LRMS (M+H+) m/z=271.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH3:9])[CH:3]=1.[O-]CC.[Na+].Br[CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1S
Reactant: CCOC(CBr)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSc1ccc(Br)cc1C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of the thiocarbamic acid S-ester (34.7 g) in THF (500 mL) under an atmosphere of nitrogen was added a solution of KOH (17.8 g, 2.5 equiv) in MeOH (90 mL), the solution allowed to stir at room temperature for 5 hr and quenched by the addition of 1N HCl, extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-bromo-2-methyl benzenethiol which was used immediately. The thiol was added dropwise to a solution of sodium ethoxide (10.3 g, 1.2 equiv) in EtOH (600 mL), allowed to stir for 30 min before the dropwise addition of 2-bromo-1,1-diethoxyethane (23 mL, 1.2 equiv). The reaction mixture was heated at reflux for 4 hr, allowed to cool and stir at room temperature overnight, then quenched by the addition of water and concentrated. Water and EtOAc were added, the phases separated, and the aqueous phase was further extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 5% EtOAC in hexanes) to give 4-bromo-1-(2,2-diethoxyethylsulfanyl)-2-methylbenzene (38.4 g, 88% for 2 steps).