Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[C:11](=[O:13])[CH3:12])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(=O)Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(F)cc1)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a room temperature suspension of sodium hydride (33.4 mmol, 1.34 g of 60% in mineral oil) in 60 mL of THF was added a solution of the N-(4-fluorophenyl)acetamide (4.1 g, 26.8 mmol) in THF (30 mL) over a 5 minute period. After 30 minutes, a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.2 mL, 26.8 mmol) in THF (10 mL) was added. After 15 hours, the reaction was concentrated in vacuo, the residue was diluted with 1 N sulfuric acid (300 mL) and extracted with three 100 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a brownish oil. The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes to afford 3.7 g of N-(4-bromo-2-nitrophenyl)-N-(4-fluorophenyl)acetamide as a thick yellow oil. MS m/z 353/355 (MH+).
Reaction SMILES: C(S)C.CN(C=O)C.[H-].[Na+].[C:11]([C:15]1[C:16]([CH3:38])([CH3:37])[CH2:17][O:18][C:19]=1[C:20]1[CH:34]=[C:33]([O:35]C)[C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=2[CH:21]=1)([CH3:14])([CH3:13])[CH3:12]>O>[C:11]([C:15]1[C:16]([CH3:38])([CH3:37])[CH2:17][O:18][C:19]=1[C:20]1[CH:34]=[C:33]([OH:35])[C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=2[CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cc(C2=C(C(C)(C)C)C(C)(C)CO2)cc2oc(-c3ccccc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCS
Solvent: CN(C)C=O
Product: CC(C)(C)C1=C(c2cc(O)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Temperature: 155 °C
Yield: 86.8 %

Procedure:
In nitrogen atmosphere at 0° C., 0.25 mL of ethanethiol was added to 3 mL of DMF dissolving 104 mg (2.6 mmol) of 60% sodium hydride. Adding 505 mg (1.3 mmol) of 4-t-butyl-5-(4-methoxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [62]), the mixture was refluxed for 1.0 hours at 155° C. The resulting mixture was poured in pure water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried with magnesium sulfate anhydride, and concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=5:1) to obtain 410 mg of 4-t-butyl-5-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [63]). Yield 82.8%.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C#CCCCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 10 g (89 mmol) of 5-hexynoic acid and 31.0 mL (223 mmol) of triethylamine in 450 mL of anhydrous tetrahydrofuran at −25° C. under an atmosphere of nitrogen was added 12 mL (98 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 4.2 g (98 mmol) of anhydrous lithium chloride and 17 g (94 mmol) of (S)-(−)-4-benzyl-2-oxazolidinone were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (500 mL) and extracted with ether (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 10-25% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (22 g, 93%). 1H NMR (500 MHz, CDCl3): δ 7.35-7.31 (m, 2H), 7.28-7.25 (m, 1H), 7.19-7.21 (m, 2H), 4.69-4.64 (m, 1H), 4.22-4.15 (m, 2H), 3.28 (dd, J=13.4, 3.3 Hz, 1H), 3.13-3.01 (m, 2H), 2.78 (dd, J=13.4, 9.6 Hz, 1H), 2.34-2.30 (m, 2H), 1.99 (t, J=2.7 Hz, 1H), 1.96-1.88 (m, 2H). LC-MS: m/z (ES) 272.2 (MH)+, 294.3 (MNa)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][C:14](O)=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].P(Cl)(Cl)([Cl:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:23][C:14]1[N:13]=[C:12]2[S:20][C:9]([S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[N:10][N:11]2[C:16](=[O:17])[C:15]=1[CH3:18]
Reactant: CCCCCCCSc1nn2c(=O)c(C)c(O)nc2s1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCCCCCCSc1nn2c(=O)c(C)c(Cl)nc2s1
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 19.5 g of the thus obtained 2-heptylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 38 g of phosphorus oxychloride and 13.6 g of phosphorus pentachloride was warmed to 77°~88° C. and was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, thereafter the residue was dissolved in toluene, and the solution was washed with a potassium carbonate aqueous solution and water respectively. After the solution was dried over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on a silica gel column with an ethyl acetate/n-hexane (2:3) mixture as an eluent. After the solvent was distilled off, 19.0 g of 7-chloro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 79°~81° C. Yield 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.CC1C=CC(N=[CH:27][C:28]2[C:29]([NH2:37])=[CH:30][C:31]3[O:35][CH2:34][O:33][C:32]=3[CH:36]=2)=CC=1>>[CH3:17][O:16][C:10]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[C:3]([O:2][CH3:1])[C:4]2[CH2:5][C:6]3[C:7]([C:8]=2[CH:9]=1)=[N:37][C:29]1[CH:30]=[C:31]2[O:35][CH2:34][O:33][C:32]2=[CH:36][C:28]=1[CH:27]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COCOc1c(OC)cc2c(c1OC)CCC2=O
Product: COCOc1c(OC)cc2c(c1OC)Cc1cc3cc4c(cc3nc1-2)OCO4
Yield: 78.7 %

Procedure:
Using the procedure of Example 1, 4,6-dimethoxy-5-methoxymethoxyindan-1-one (100 mg, 0.4 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (101 mg, 0.4 mmol) to yields 7,9-dimethoxy-8-methoxymethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (120 mg, 79% of theory). This material was used directly in part (B).
Reaction SMILES: O[N:2]1[C:11]([CH3:12])=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].P(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:12][C:11]1[NH:2][C:3](=[O:17])[C:4]2[C:9]([C:10]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1c(CC(=O)O)c2ccccc2c(=O)n1O
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Product: Cc1[nH]c(=O)c2ccccc2c1CC(=O)O
Temperature: 0 °C

Procedure:
1,2-Dihydro-2-hydroxy-3-methyl-1-oxo-4-isoquinoline acetic acid (4.0 g., 17.2 mmol) dissolved in 30 ml. ethyl acetate at 0° was reacted with phosphorous trichloride (1.50 ml., 17.2 mmol). The mixture was heated at 80° for 1.5 hr then poured onto 100 g. of ice water, stirred for 16 hr and filtered yielding a light yellow crude product; 3.307 mg (89%) mp 280°-295° d. Recrystallization from acetic acid afforded analytically pure material of mp 295°-300° d.
Reaction SMILES: ClC1OC([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=C(C2C=CC=CC=2)N=1.COC1(C2C=C(C=CC=2)CS)CCOCC1.C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C>[C:16]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(Cl)nc2-c2ccccc2)cc1
Agent: COC1(c2cccc(CS)c2)CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[(2-chloro)-4-phenyloxazol-5-yl]benzenesulfonamide (0.21 g, 0.63 mmol) in 2 mL of anhydrous THF at 5° C. was added a solution of 3-[tetrahydro-(4-methoxy)pyran-4-yl]benzyl mercaptan (prepared as described in U.S. Pat. No. 5,424,320) (0.15 g, 0.63 mmol) and DBU (95 mg, 0.63 mmol) in 5 mL of THF while maintaining the temperature at 5° C. The reaction mixture was stirred for 1 h at 5° C. for 5 h at room temperature. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (1×100 mL), brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 40% ethyl acetate in hexane, to give 0.19 g (56%) of 4-[2-[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl]methylthio]-4-phenyloxazol-5-yl]benzenesulfonamide as a white solid: m.p. 74.7–78.5° C. 1H NMR (CDCl3/300 MHz) δ 1.85–1.97 (m, 4H), 2.92 (s, 3H), 3.71–3.85 (m, 4H), 4.48 (s, 2H), 4.87 (s, 2H), 7.29–7.47 (m, 7H), 7.60–7.69 (m, 4H), 7.86–7.90 (m, 2H). HRMS calcd for C28H28N2O5S2 537.1518. Found 537.1516.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>O1CCCC1.O>[C:17]([C:7]1[CH:6]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:4]=[CH:3][C:2]=1[F:1])([OH:19])=[O:18]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1F
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 4-fluorobenzotrifluoride (75 ml) in tetrahydrofuran (570 ml) under a nitrogen atmosphere and at a temperature of approximately -60° C. was added butyl lithium (25N, 200 ml) over a period of one hour. The reaction mixture was stirred at from -70° to -60° C. for four hours and then was poured over an excess of dry ice. After fifteen minutes the excess dry ice was evaporated and the solvent removed to leave a residue. The residue was taken up in water (500 ml) and sodium hydroxide (1N, 30 ml) prior to washing with ethyl acetate (2×300 ml). The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2x300 ml). Finally, the combined organic extracts were washed with water (500 ml), dried and then evaporated to yield a crude residue which, upon recrystallisation from toluene/hexane, gave the title compound as a solid (77 g, 0.37 mol, 81% yield).
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:13][C:14](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:7]([N:13]=[C:14]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCNC(=N)N
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 4.5 g. of sodium, 38.4 g. of n-hexylguanidine sulfate, and 25.4 g. of n-hexyl isocyanate, there was obtained 11.1 g. of 1-n-hexylamidino-3-n-hexylurea having the structural formula ##STR62## as a white crystalline solid which melted at 75°-78° C. The solubility of this base in water at 25° C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25° C. it was soluble to the extent of 5 percent (w/v); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[O:6]C2C=CC=CC=2)[CH2:3][CH2:2]1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[CH:30]=[CH:29][N:28]=2)=[O:25])[CH2:17][CH2:16]1.[H-].[Na+].CN(C)C=O>O>[CH:1]1([NH:4][C:5]([N:39]2[C:40]3[C:36](=[CH:35][C:34]([O:33][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([NH:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:18]5[CH2:17][CH2:16][CH:15]([OH:14])[CH2:20][CH2:19]5)[CH:32]=4)=[CH:42][CH:41]=3)[CH:37]=[CH:38]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(CCCN1CCC(O)CC1)Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: O=C(NC1CC1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC(O)CC1)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 25 °C

Procedure:
Phenyl N-cyclopropylcarbamate (120 mg) was added to a solution of 260 mg of 5-[(2-{[4-(4-hydroxypiperidino)butanoyl]amino}-4-pyridyl)oxy]indole, 53 mg of sodium hydride (60% in oil) and 5 ml of dimethylformamide while stirring at room temperature. After stirring for 10 minutes, water was added and extraction was performed with ethyl acetate. NH type silica gel was added to the ethyl acetate layer, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and purification was performed by column chromatography (chloroform:methanol=30:1). The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed twice with 1N aqueous sodium hydroxide. After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 20 mg of the target substance as a white powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.FC(F)(F)C(O)=O.[CH2:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])[CH2:53][CH2:54][CH3:55].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:12](=[O:14])[C@@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:61][CH2:60]1)=[O:58])[CH2:53][CH2:54][CH3:55]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
To a solution of 5 g of (S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyric acid, 7.4 g of NEM and 5.3 g of TOTU in 35 ml of DMF, 4.8 g of Piperazine-1-carboxylic acid butyl ester trifluoroacetate was added at RT and stirred for 16 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 250 ml of ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 6.3 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
12-Hydroxydodecanoic acid (2.16 g, 10.0 mmol) was suspended in 20mL of dry THF. After the addition of 1.39g (16.5 mmol) of dihydropyran, the solution was stirred for 10 min. at room temperature. Twenty mg (0.105 mmol) of crystalline p-toluenesulfonic acid monohydrate was then added. The mixture became clear immediately, and was stirred for an additional 2 hours at room temperature. Evaporation of solvent under reduced pressure afforded a crude product which was purified by flash chromatography (CHCl3) to yield 2.40 g (80%) of 12-(tetrahydropyranyloxy)dodecanoic acid as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29]5([CH2:34][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)OCC[O:30]5)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)(=O)C.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29](=[O:30])[CH2:34][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCC2(C4)OCCO2)ccc1OCc1ccccn1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 177.3 %

Procedure:
To a stirring acetic acid/H2O solution (4:1, 250 mL) was added N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine hydrochloride (10.0 g, 19.3 mmol), and the contents heated at 80° C. for 40 h. The dark colored mixture was cooled to rt, and the solvent removed under reduced pressure. The crude residue was suspended in water (200 mL), stirred for 10 min., and filtered. The collected solid was further washed with H2O (300 mL) and ether (100 mL) to afford the desired product as a brown solid (8.1 g, 89%). 1H-NMR (DMSO-d6) δ 8.71 (d, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.10 (td, 1H), 7.78 (d, 1H), 7.75 (d, 1H), 7.56 (m, 2H), 7.25 (d, 1H), 5.38 (s, 2H), 5.08 (br, 1H), 3.76 (s, 2H), 3.50 (t, 2H), 2.69 (t, 2H); LCMS RT=2.44 min; [M+H]+=437.3.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][OH:13])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[OH:13][CH2:12][CH2:11][C:10]1[CH:14]=[CH:15][C:7]([NH:6][C:3](=[O:4])[O:2][CH3:1])=[CH:8][CH:9]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc(CCO)cc1
Yield: 34.3 %

Procedure:
9.45 g (0.1 mole) methylchloroformate was added to a solution of 13.72 g (0.1 mole) p-aminophenethyl alcohol and 8.4 g (0.1 mole) pyridine in dichloromethane at 0° C. The reaction was stirred between 0° C. and room temperature, and when completed, poured onto ice water and the product was extracted with ethyl acetate, dried and the solvent was evaporated in vacuo to give 6.7 g (yield 34.7%) of methyl N-[4-(2-hydroxyethyl)phenyl]carbamate.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][NH:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[N:11]([O-])=[O:12].[Na+]>CC(O)=O.O>[CH3:1][C:2]1([CH3:10])[CH2:6][N:5]([N:11]=[O:12])[CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=N[O-]
Reactant: CC1(C)CNC(C(=O)O)C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(C(=O)O)N(N=O)C1
Reaction time: 3 h

Procedure:
To a suspension of 37.5 g of the crude 4,4-dimethylpyrrolidine-2-carboxylic acid in 420 mL of AcOH was added a solution of 13.3 g (0.19 mol) of NaNO2 in 210 mL of water over 15 min at room temperature and stirred for 3 h. The solution was concentrated under reduced pressure. Acetone (250 mL) was added to the residue and the precipitate was filtered off, and the solution was concentrated under reduced pressure to dryness and crude 4,4-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid was obtained as brown oil.
Reaction SMILES: Cl.[CH2:2]([O:6][CH:7]1[CH2:10][NH:9][CH2:8]1)[CH2:3][CH2:4][CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:42]=[C:43]1[NH:52][C:51]2[N:50]=[CH:49][C:48](/[CH:53]=[CH:54]/[C:55](O)=[O:56])=[CH:47][C:46]=2[CH2:45][CH2:44]1>CN(C)C=O.O.C(OCC)(=O)C>[CH2:2]([O:6][CH:7]1[CH2:10][N:9]([C:55](=[O:56])/[CH:54]=[CH:53]/[C:48]2[CH:47]=[C:46]3[C:51](=[N:50][CH:49]=2)[NH:52][C:43](=[O:42])[CH2:44][CH2:45]3)[CH2:8]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h

Procedure:
3-Butoxyazetidine hydrochloride (100 mg, 0.6 mmol), EDCI (113 mg, 0.6 mmol), HOBt (80 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100 mg, 0.4 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight and then partioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted successively with ethyl acetate (2×20 mL) and dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (99:1 to 97:3) as eluent. The title product was obtained as a grey solid (30 mg, 23%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13]C=2)(C)C)=[CH:4][CH:3]=1.CC(C1C=CC(OCC2OC2)=CC=1)(C1C=CC([O:27]CC2OC2)=CC=1)C.C(P(CCCC)CCCC)CCC>>[CH:7]1[CH:6]=[C:5]([C:8]2[CH:11]=[CH:16][CH:15]=[C:14]([OH:17])[CH:13]=2)[C:4]([OH:27])=[CH:3][CH:2]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: CCCCP(CCCC)CCCC
Product: Oc1cccc(-c2ccccc2O)c1

Procedure:
152 g of bisphenol A, 63 g of a diglycidyl ether of bisphenol A having an epoxy equivalent weight of 189 and 0.1 g of tributylphosphine were heated at 160° C. for 1 hour. Afterwards the epoxy was no longer detectable, and a chain-extending diphenol had formed. 53.8 g of isopropanol, 129 g of di-n-butylamine, 31.5 g of paraformaldehyde and 17.6 g of isobutanol were added and the mixture was heated at 80° C. for 2 hours. The product had a solids content of 80% by weight.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:26]3[C:25]4[CH:24]=[C:23]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]([CH3:33])[C:15]2=[O:34])=[CH:10][CH:9]=1)(C)(C)C.Cl.N1C=CC=CC=1.[S:44](Cl)([CH3:47])(=[O:46])=[O:45]>O1CCOCC1.C(Cl)Cl>[CH3:6][N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:26]3[C:25]4[CH:24]=[C:23]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]([CH3:33])[C:15]2=[O:34])=[CH:10][CH:9]=1)[S:44]([CH3:47])(=[O:46])=[O:45]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-n2c(=O)n(C)c3cnc4ccc(-c5cccnc5)cc4c32)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CN(c1ccc(-n2c(=O)n(C)c3cnc4ccc(-c5cccnc5)cc4c32)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
62 mg (0.128 mmol) of methyl-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-carbamic acid tert-butyl ester (Example 50a) is treated with 2.5 ml of 1 M HCl in dioxane at rt for 1 h, and then the solution is evaporated to dryness. The residue is taken in 2 ml of CH2Cl2 together with 414 μl (5.13 mmol) of pyridine and 66 mg (0.579 mmol) of mesylchloride (Fluka, Buchs, Switzerland). The solution is stirred at rt for 17.5 h, then 15 mg (0.129 mmol) of mesylchloride are added and the reaction mixture is stirred at rt for 5.5 h. The reaction is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with brine, dried over Na2SO4, filtered and evaporated. The residue is purified by preparative HPLC to give the title compound as a yellowish solid. ES-MS: 460 (M+H)+; analytical HPLC: tret=2.25 min (Grad 1).