Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:12][C@H:3]([CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][NH:1][CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccnc4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
(2S)-1-Amino-3-(3-pyridinyloxy)-2-propanol (0.21 g, 1.25 mmol) (which was obtained in Example 124) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) (0.413, 1.25 mmol) were mixed in N,N-dimethylformamide (12 mL) and then treated with sodium triacetoxyborohydride (0.56 g, 2.5 mmol) and acetic acid (0.26 mL). After stirring, at room temperature under a nitrogen atmosphere for one day, the mixture was purified by column chromatography (dichloromethane/methyl alcohol 85/5) to give the title compound as a yellow solid (0.25 g, 56% yield); mp; 130–132° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20–1.54 (m, 2 H), 1.90–2.02 (m, 2 H), 2.67 (t, 2 H), 2.78–2.97 (m, 4 H), 3.22–3.26 (m, 1 H), 3.35 (brs, 2 H), 3.64–3.70 (d, 2 H), 3.97–4.08 (m, 3 H), 4.60–4.63 (m, 1 H), 6.84–6.86 (m, 2 H), 7.03–7.05 (m, 2 H), 730–7.36 (m, 1 H), 7.38–7.40 (m, 1 H), 8.16–8.17 (m, 1 H), 8.8.29–8.30 (m, 1 H); MS (ES) m/z: 457 (MH+).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:23][C:24]1[C:33]([F:34])=[C:32](F)[C:31]([O:36][CH3:37])=[C:30]2[C:25]=1[C:26](=[O:44])[C:27]([C:41]([OH:43])=[O:42])=[CH:28][N:29]2[CH:38]1[CH2:40][CH2:39]1>N1C=CC=CC=1>[NH2:23][C:24]1[C:33]([F:34])=[C:32]([N:9]2[CH2:10][CH2:11][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]2)[C:31]([O:36][CH3:37])=[C:30]2[C:25]=1[C:26](=[O:44])[C:27]([C:41]([OH:43])=[O:42])=[CH:28][N:29]2[CH:38]1[CH2:40][CH2:39]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: COc1c(N2CCC(n3ccnn3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 120 °C

Procedure:
3-(1,2,3-triazol-1-yl)pyrrolidinehydrochloride (147 mg, 0.84 mmol) and DBU (128 mg, 0.84 mmol) were added to a suspension of 5-Amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.33 mmol) in pyridine (5 ml). The reaction mixture was heated at 120° C. for 30 hrs, concentrated and the residue was triturated with water. The separated solid was filtered, washed with water and recrystallized from chloroform-hexane. Yield 40 mg; m.p. 208° C.; 1H NMR (TFA) δ: 9.39 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 5.88 (s, 1H), 4.43-4.73 (m, 4H), 4.10 (m, 1H), 3.79 (s, 3H), 2.92 (m, 2H), 1.12-1.58 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:20][O:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)([OH:24])(=[O:23])=[O:21].[CH3:1][CH:2]1[N:6]([CH3:20])[C:5]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:4]=2[S:3]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2ccc(S(=O)(=O)N3CCCCC3)cc2s1
Product: CC1Sc2cc(S(=O)(=O)N3CCCCC3)ccc2N1C
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of Compound 3 (1.0 g, 3.4 mmol) and p-toluenesulfonic acid methyl ester (0.94 g, 5.1 mmol) was heated in a pressure tube at 130° C. for 1 hour. The mixture was allowed to cool to room temperature, and the resulting mass was triturated with acetone (25 ml) until a gray colored solid separated. The solid was collected by centrifugation, washed with acetone and dried under vacuum to yield 1.4 g (86%) of Compound 4 whose structure is given below:
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[I-].[Na+].[Cs].[C:35]([N:42]1[CH2:50][CH2:49][CH:45]([C:46]([OH:48])=[O:47])[CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(#N)C>[C:38]([O:37][C:35]([N:42]1[CH2:50][CH2:49][CH:45]([C:46]([O:48][CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]2[O:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]4)=[C:15]([F:27])[CH:14]=3)[CH2:8]2)=[O:47])[CH2:44][CH2:43]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: [Cs]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 72 %

Procedure:
To (R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (751.8 mg, 1.58 mmol) and sodium iodide (236.0 mg, 1.58 mmol) in acetonitrile (30 mL), is added the cesium salt of N-BOC-isonipecotic acid (884.2 mg, 2.45 mmol). The mixture is heated to reflux overnight. After cooling to RT, the mixture is filtered and washed with dichloromethane. The filtrate is diluted with CH2Cl2 and water and the layers are separated. The aq layer is extracted with dichloromethane twice and the combined organic layers are washed with water, brine, dried over sodium sulfate and conc in vacuo. Purification by silica gel chromatography gave the title compound in 72% yield (757.3 mg, 1.13 mmol). 1H NMR (400 MHz, CDCl3): δ 7.47 (dd, 1H), 7.24 (t, 1H), 7.14 (dd, 1H), 5.88 (s, 2H), 4.78-4.85 (m, 1H), 4.18 (dd, 1H), 4.08 (t, 2H), 4.03 (dd, 2H), 3.67 (dd, 1H), 3.13-3.20 (m, 4H), 3.10 (dt, 1H), 2.83 (t, 2H), 2.60 (tt, 1H), 2.59 (s, 3H), 2.35-2.46 (m, 2H), 2.17-2.23 (m, 2H), 1.90-1.96 (m, 2H), 1.57-1.686 (m, 2H) 1.45 (s, 9H). MS-APCI (m/z+): 570.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: BrCCC1CCOCC1
Product: Cl
Product: O=C1OC2(CCN(C(=O)c3cn(CCC4CCOCC4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 4-(2-bromo-ethyl)-tetrahydro-pyran (described in US 2004220214) gave the title compound. ES-MS m/e (%): 511.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:18]([N:5]1[C:6]([CH:7]=[O:8])=[C:2]([Cl:1])[N:3]=[C:4]1[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-5-formyl-2-(4-nitrophenyl)imidazole (19.7 g, 78.3 mmol), benzyl bromide (14.5 g, 85.0 mmole) and potassium carbonate (11.7 g, 85.0 mmole) in DMF (150 ml) was heated to 110° C. for 1.5 hours. The mixture was evaporated and residue was poured into cold water and was allowed to stay overnight in the refrigerator. The tarry residue was pulverized and filtered. Yield of crude title compound: 33.4 g. The product was recrystallized from ethanol (96%, 350 ml). Yield: 14.0 g. NMR confirmed the structure of the title compound, Compound 7.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Br:15][C:16]1[CH:17]=[N:18][C:19](I)=[N:20][CH:21]=1>>[Br:15][C:16]1[CH:17]=[N:18][C:19]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:20][CH:21]=1
Reactant: Brc1cnc(I)nc1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc(Br)cn1
Yield: 56 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (55 mg, 0.30 mmol) was converted (using 5-bromo-2-iodo-pyrimidine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 58 mg, 56%) which was obtained as a light yellow solid. MS: m/e=341.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15].[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29]([CH3:31])=O>C(O)C>[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]([C:28]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[Cl:1])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:29]=1[CH3:31])=[O:32]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OCCCCCCO
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCO)C1c1cccc(Cl)c1Cl
Yield: 38 %

Procedure:
35.0 g (0.20 mole) of 2,3-dichlorobenzaldehyde, 23.0 g (0.20 mole) of methyl 3-aminocrotonate, 40.0 g (0.20 mole) of acetoacetic acid 6-hydroxyhexyl ester and 100 ml of ethanol were mixed and heated at reflux for 6 hours, and the resultant product was chromatographed on a silica gel column to obtain 34.7 g (yield 38.0%) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-hydroxyhexyl ester as an oil. 13.7 g (0.03 mole) of this oil was dissolved together with 11.4 g (0.06 mole) of tosyl chloride in 100 ml of chloroform, to which was added dropwise 7.1 g (0.09 mole) of pyridine under ice cooling with stirring. This mixture was allowed to stand at room temperature for 2 hours, then 100 ml of water was added thereto, and stirring was continued for 3 hours. The chloroform layer of the resultant reaction mixture was separated, washed with 100 ml of 0.02 N sulfuric acid, 100 ml of water and 100 ml of saturated aqueous sodium bicarbonate successively, and dried over anhydrous sodium sulfate. This solution was concentrated, and the resultant residue was chromatographed on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 150:1) as an eluent to obtain 16.3 g (yield 89.0%) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester. The IR and PMR spectra of this product were as follows.
Reaction SMILES: C[N:2]([C:4](F)(F)[CH:5]([F:7])[F:6])C.[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:22][NH:23]N>C(#N)C>[CH2:17]([O:16][C:14]([C:13]1[C:4]([CH:5]([F:7])[F:6])=[N:2][N:23]([CH3:22])[C:12]=1[C:11]([F:21])([F:20])[F:10])=[O:15])[CH3:18]
Reactant: CN(C)C(F)(F)C(F)F
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)F)nn(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
(0.34 g, 5 mmol) as a 17% solution in acetonitrile (0.76 ml) was added to a solution of TFEDMA (0.59 ml, 5.0 mmol) in CH3CN (5 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min. In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (0.73 ml, 5.0 mmol) was added to a solution of potassium fluorides (0.88 g, 15.0 mmol) in dry acetonitrile (10 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. Methyl hydrazine (0.32 ml, 6.0 mmol) was then added dropwise at room temperature and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1-8:2). N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.95 g) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1-c1ccc(F)cc1

Procedure:
A mixture of methyl 2-chloropyridin-3-carboxylate (6.8 g.), 4-fluorobenzeneboronic acid (7.2 g.), 1M. aqueous sodium carbonate (40 ml.), Pd(dppb)Cl2(1.2 g.), ethanol(10 ml.) and toluene(150 ml.) was stirred at reflux under an inert atmosphere for 5 hr. The reaction was then cooled, the oganic layer separated, the aqueous extracted with toluene and then the Icombined extracts dried and evaporated to dryness. The product was purified by flash column chromatography eluting wth ethyl acetate/iso-hexane(9:1,8:2,7:3) to give methyl 2-(4-fluorophenyl)pyridin-3-carboxylate as a white solid(7.5 g.)
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[CH:14]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]([CH:39]1CCCCC1)[CH:33]1CCC[CH2:35][CH2:34]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[CH2:1]([N:8]1[CH:17]=[C:16]([CH2:35][CH2:34][CH2:33][N:32]([CH3:39])[CH3:31])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[CH:14]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccccc4)cc(Br)c3c2)c1
Reactant: CN(C1CCCCC1)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccccc4)cc(CCCN(C)C)c3c2)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step i) (170 mg), tetrabutylammonium chloride (10 mg), Pd-118 (24 mg) and N-methyldicyclohexylamine (0.12 mL) in N,N-dimethylacetamide (3 mL) was evacuated and flushed with nitrogen (×3) before the addition of allyl alcohol (0.05 mL). The resultant solution was stirred under nitrogen at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and dilute hydrochloric acid (1N, 2 mL) was added, followed by dichloromethane (10 mL). The resulting suspension was filtered and the filtrate was washed with water (2×5 mL). The organic phase was separated and treated with dimethylamine hydrochloride (0.181 g) followed by sodium triacetoxyborohydride (0.157 g). The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was filtered and poured directly onto a silica column (10 g) (eluting with 3% methanol in dichloromethane) to afford the sub-titled compound (0.12 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[N:4]=1.[CH2:18](O)[CH3:19]>>[CH3:17][S:14]([NH:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([CH2:2][N:4]([CH2:3][CH2:2][C:19]1[CH:18]=[CH:9][C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1)[CH3:5])[CH:12]=[CH:11]2)(=[O:16])=[O:15]
Reactant: CCO
Reactant: CS(=O)(=O)Nc1ccc2nc(CCl)ccc2c1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc(NS(C)(=O)=O)ccc2n1

Procedure:
4-[2-(Methylamino)ethyl]methanesulphonanilide (0.228 g, 1 mmol - see Preparation 14(B)) and 2-chloromethyl-6-methanesulphonamidoquinoline (0.135 g, 0.5 mmol - see Preparation 12(D)) were heated in ethanol solution (5 ml) at reflux for 4 hours. The solvent was then evaporated in vacuo and the residue dissolved in methylene chloride, washed with water, dried (MgSO4), filtered and evaporated in vacuo. The resulting gum was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated in vacuo to give a foam which crystallised from ethanol, yield of the title compound 0.45 g, m.p. 165°-166°, confirmed spectroscopically to be identical to the product of Example 5.
Reaction SMILES: C(C1C=C(C=C(C(C)(C)C)C=1O)C(OCC[CH2:13][N:14]([CH3:16])[CH3:15])=O)(C)(C)C.[C:25]1([CH3:36])[CH:30]=[CH:29][C:28]([S:31]([O:34]C)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(#N)C>[S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:36])=[CH:26][CH:27]=1)([O-:34])(=[O:33])=[O:32].[CH3:13][NH+:14]([CH3:16])[CH3:15]
Reactant: CN(C)CCCOC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Product: C[NH+](C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A mixture of 16.78 g (50 mmol) of 3-dimethylaminopropyl 3,5-di-tert-butyl-4-hydroxybenzoate, prepared as described in Example 4, 9.31 g (50 mmol) of methyl p-toluenesulfonate and 125 ml of acetonitrile was heated at reflux for 1 hour and 15 minutes and cooled. The collected solid was recrystallized from 140 ml of acetonitrile to give 19.48 g (74.7% of theory) of N-[3-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)propyl)]trimethyl ammonium tosylate.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[N:19]1([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: ClC(c1ccccc1)c1ccc2cccnc2c1
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccc3cccnc3c2)n2ccnc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 33.2 %

Procedure:
A mixture of 3.4 parts of 7-[chlorophenylmethyl]quinoline, 4.5 parts of 1H-imidazole and 72 parts of N,N-dimethylformamide was stirred for 6 hours at 80° C. The reaction mixture was evaporated to dry and the residue was taken up in water. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 1.27 parts (33.2%) of 7-[(1H-imidazol-1yl)phenylmethyl]quinoline; mp. 110.7° C. (compound 36).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][C:15]([CH3:22])=[CH:14]2>CC(O)=O>[Br:8][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:17](=[O:21])[NH:16][C:15]=1[CH3:22]
Reactant: COc1ccc2c(=O)[nH]c(C)cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(C)c(Br)c2c1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
NBS (6.9 g, 40 mmol) is added in one portion to ice-cold suspension of 6-methoxy-3-methyl-2H-isoquinolin-1-one (6.7 g, 35 mmol) in AcOH (100 ml). The ice bath is removed, and after 1 h, the mixture is concentrated in vacuo. The residue is diluted with water (40 ml) and basified with 10N—NaOH to pH 12. The resulting white solid is filtered and dried to give 9.3 g of 4-bromo-6-methoxy-3-methyl-2H-isoquinolin-1-one. 1H NMR (CDCl3) 8.10 (d, 1H), 7.14 (s, 1H), 7.08 (d, 1H), 3.89 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]1[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][C:7]([NH2:13])=[CH:6][C:5]=2[CH2:4]1.CC1(C)[O:28][C:27](=O)[CH:26]=[C:25]([CH3:30])[O:24]1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:3]1[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][C:7]([NH:13][C:27](=[O:28])[CH2:26][C:25](=[O:24])[CH3:30])=[CH:6][C:5]=2[CH2:4]1
Reactant: CN(CCc1ccccc1)C1CCc2ncc(N)cc2C1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cnc2c(c1)CC(N(C)CCc1ccccc1)CC2
Temperature: 120 °C
Yield: 71.1 %

Procedure:
A 10 mL vial, equipped with a magnetic stirrer, was charged with N6-methyl-N6-(2-phenylethyl)-5,6,7,8-tetrahydroquinoline-3,6-diamine (79 mg, 0.281 mmol), 2,2,6-trimethyl-4H-1,3-dioxin-4-one (48 mg, 0.337 mmol), and toluene (3 mL). The vial was sealed and heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (0 to 100% acetone in hexanes) to give the title compound (73 mg, 71%). MS [M+H]+=366.2 m/z.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([O:12][CH3:13])=[O:11].CI.[CH3:16]C(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:16][C:2]1([C:10]([O:12][CH3:13])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: COC(=O)C1Cc2ccccc2O1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1(C)Cc2ccccc2O1
Temperature: 25 °C

Procedure:
To a solution of methyl 2,3-dihydrobenzofuran-2-carboxylate (Step A, 1.0 g, 5.5 mmol) and methyl iodide (1.8 mL, 28 mmol) in 20 mL of anhydrous tetrahydrofuran at −78° C. was added potassium tert-butoxide (1 M in tetrahydrofuran, 8.4 mL, 8.4 mmol). The reaction was allowed to warm to room temperature overnight, and the resulting mixture was diluted with ethyl acetate (100 mL), washed with aqueous saturated ammonium chloride (100 mL) and water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography eluted with 2-5% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.16 (d, 1H), 7.12 (t, 1H), 6.86 (t, 1H), 6.76 (d, 1H), 3.75 (s, 3H), 3.58 (d, 1H), 3.17 (d, 1H), 1.66 (s, 3H).