Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1>>[OH:32][C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[N:20][C:12]=2[O:11][C:8]2[CH:9]=[CH:10][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: Cc1noc2ccc(Oc3ncccc3C(=O)O)cc12
Reactant: CC(C)(O)c1ccc(CN)cc1
Product: Cc1noc2ccc(Oc3ncccc3C(=O)NCc3ccc(C(C)(C)O)cc3)cc12

Procedure:
Prepared from 2-(3-Methyl-benzo-(d)isoxazol-5-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. mp 128-30° C. MS (m/e): 418 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][C:3]=1[F:20].S(=O)(=O)(O)O.BrC1C=CC2OC3C(=CC(OC)=CC=3)C(=O)C=2C=1F>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:6][C:7]3[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:9](=[O:11])[C:18]=2[CH:19]=1
Reactant: COc1ccc(Oc2ccc(Br)c(F)c2)c(C(=O)O)c1
Agent: COc1ccc2oc3ccc(Br)c(F)c3c(=O)c2c1
Agent: O=S(=O)(O)O
Product: COc1ccc2oc3cc(F)c(Br)cc3c(=O)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a 1 L flask charged with 2-(4-bromo-3-fluorophenoxy)-5-methoxybenzoic acid (100 g, 293 mmol) was added sulfuric acid (391 mL, 7329 mmol). The resulting slurry was heated to 80° C. for 2 hours. The reaction was removed from the oil bath, cooled to rt and poured into a 3 L flask containing 2 L of ice water. The derived slurry was vigorously stirred for 2 hours before being filtered. The derived solid was washed well with water (3×500 mL), 3 N NaOH (2×500 mL) and water (2×500 mL). The wet solid was then washed with ether (2×250 mL) and dried under a vacuum at 50° C. overnight. The solid was then azeotropped from toluene (3×100 mL) to provide 41 g of a 4:1 mixture of 2-bromo-1-fluoro-7-methoxy-9H-xanthen-9-one:2-bromo-3-fluoro-7-methoxy-9H-xanthen-9-one (40.0 g, 123.9 mmol, 42.2% yield). A portion of this material (10 g) was slurried in hot IPA (200 mL) and placed in the refrigerator overnight. The derived solid was filtered and purified by silica gel chromatography (100% CH2Cl2) to provide 2-bromo-1-fluoro-7-methoxy-9H-xanthen-9-one (4.1 g) and 2-bromo-3-fluoro-7-methoxy-9H-xanthen-9-one (0.95 g) both as light white solids.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:11])[C:4](=[S:10])[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:12](OCC)(OCC)(OCC)[CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[CH2:13]([C:14]1[NH:9][C:7](=[O:8])[C:6]2[S:5][C:4](=[S:10])[N:3]([CH3:11])[C:2]=2[N:1]=1)[CH3:12]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Cn1c(N)c(C(N)=O)sc1=S
Solvent: CC(=O)OC(C)=O
Product: CCc1nc2c(sc(=S)n2C)c(=O)[nH]1
Yield: 65 %

Procedure:
The general procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966) was used to prepare 4-amino 3-methylthiazoline-2-thione-5-carboxamide, of which 27.3 g (0.14 mole) was suspended in a mixture of approximately 144ml of acetic anhydride and about 144ml of triethyl orthopropionate. The resultant mixture was refluxed for approximately one half hour, then cooled in an ice bath. The solid which precipitated was separated by filtration, washed with diethyl ether and dried in a vacuum oven at approximately 100° C. to provide 21.4g (65%) of 5-ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. Infrared spectral analysis confirmed the structural assignment.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([O:39][C@H:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:41][C:42]([OH:44])=O)(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(Cl)CCl.CI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:24]([O:39][C@H:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:41][C:42]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:44])(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)[Si](OCCCCN)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NCCCCO
Yield: 80.9 %

Procedure:
In the same manner as described in Example 20-(1), 4-amino-1-(t-butyldiphenylsilyloxy)butane (500 mg, 1.53 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (695 mg, 1.53 mmol) in the presence of EDC MeI (595 mg, 2.0 mmol) and then deprotected with TBAF (1.0 M in THF, 2.5 mL, 2.5 mmol) in THF (15 mL) to afford 651 mg (81%) of 4-[(R)-3-tetradecanoyloxytetradecanoylamino]-1-butanol as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:16].[H-].[Na+].[CH3:19]I>COCCOC>[CH3:1][C:2]1([CH3:19])[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:16]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2C

Procedure:
By following the procedure described in Example 5, Step E, using as the reactants 2,3-dimethyl-5-methoxy-6,7-dichloro-1-indanone (13 g., 0.05 mole), sodium hydride (1.44 g., 0.06 mole), 1,2-dimethoxyethane (500 ml.) and methyl iodide (8 ml.), there is obtained 2,2,3-trimethyl-5-methoxy-6,7-dichloro-1-indanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:16])[C:13]=1[CH:14]=[O:15].C(=O)([O-])[O-:18].[K+].[K+].[K].[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:16])[C:13]=1[C:14]([OH:18])=[O:15]
Reactant: COc1ccccc1-c1ncn(C)c1C=O
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccccc1-c1ncn(C)c1C(=O)O
Reaction time: 24 h
Yield: 47.9 %

Procedure:
To a soln. of 4-(2-methoxyphenyl)-1-methyl-1H-imidazole-5-carbaldehyde (78 mg, 0.361 mmol) in acetone (5 ml) and water (1 ml) was added potassium carbonate (100 mg, 0.721 mmol). After potassium was dissolved, KMnO4 (123 mg, 0.776 mmol) was added at r.t. The mixture was stirred for 24 hrs. LC/MS showed the completion. The mixture was filtered through celite, washed w/water. The actone was evaporated from the filtrate which was extracted with EtOAc (2×). The aq. layer was acidified w/HOAc to PH=5, reduced the volume to half volume, feezed and lyphilized to leave solid, which was purified by Pre-HPLC to afford the title compound (41 mg, 0.173 mmol, 48% yield). 1H-NMR (MeOD), δ: 8.06 (s, 1H), 7.41-7.36 (m, 2H), 7.05-6.99 (m, 2H), 3.98 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([O:54][C:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=2)[CH:51]=[CH:52][CH:53]=1>CN(C)C=O>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[C:11]([NH:61][C:58]1[CH:57]=[CH:56][C:55]([O:54][C:50]2[CH:51]=[CH:52][CH:53]=[C:48]([O:47][CH3:46])[CH:49]=2)=[CH:60][CH:59]=1)=[O:13]
Reactant: COc1cccc(Oc2ccc(N)cc2)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (1.7 g, 8.36 mmol) in dry N,N-dimethylformamide (35 mL), DIPEA (2.434 mL, 13.94 mmol) and then TBTU (2.80 g, 8.71 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature. (4-{[3-(methyloxy)phenyl]oxy}phenyl)amine (1.5 g, 6.97 mmol) was then added and the reaction mixture was stirred overnight at the same temperature. The reaction was quenched with brine (100 mL) and extracted with ethyl acetate (twice 150 mL). The organic layer was washed with ice cold brine (3 times 100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP column) using as eluent a gradient and cyclohexane/ethyl acetate from 100/0 to 70/30 to afford the title compound as a white solid (1.90 g).
Reaction SMILES: C[S:2][CH2:3][CH2:4][C@@H:5]([OH:8])[CH2:6]O.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.CCCCCC.[SH+]1CCCC1>N1C=CC=CC=1.C(OCC)(=O)C>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][C@@H:5]2[CH2:4][CH2:3][S:2][CH2:6]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSCC[C@@H](O)CO
Agent: C1CC[SH+]C1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCSC2)cc1

Procedure:
(R)-4-(methylthio)1,2-butanediol (1.0 , 7.35 mmol) and p-toluenesulfonyl chloride (3.0 g, 15.8 mmol) were combined in 10 ml of pyridine at 0.5° C., then stirred at room temperature, at which time tlc (3:1 hexane:ethyl acetate) indicated no diol (Rf 0.1), appreciable of th ediol ditosylate (Rf 0.53), some intermediate thiolanium salt (Rf 0.03) and a trace of title product (Rf 0.72). The reaction mixture was then heated at 60° C. for 8 hours, at which time tlc (5:1 hexane:ethyl acetate) indicated an appreciable amount of the desired title product (Rf 0.45 ), only a trace of the ditosylate (Rf 0.22), some probable thiolanium salt (Rf 0.0), and other, generally less polar impurities. The cooled reaction mixture was diluted with an equal volume of water and two volumes of ethyl acetate. The organic layer was separated, washed with saturated NaCl, dired (MgSO4), stripped and the residue chromatographed on silica gel using 10:1 g less polar impurities (stench-) and 0.25 g of present, purified title product; tlc Rf 0.55 (4:1 hexane:ethylacetate); [alpha]D =+15.87 (c=0.6, CH3OH).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]([C:18]1[C:31]2[CH2:30][C:29]3[C:24](=[C:25]([CH2:41][CH2:42][CH3:43])[C:26]([CH2:38][CH2:39][CH3:40])=[C:27]([CH2:35][CH2:36][CH3:37])[C:28]=3[CH2:32][CH2:33][CH3:34])[CH2:23][C:22]=2[C:21]([CH2:44][CH2:45][CH3:46])=[C:20]([C:47]([O:49][CH3:50])=[O:48])[C:19]=1[C:51]([O:53][CH3:54])=[O:52])[CH2:16][CH3:17]>C1C=CC=CC=1>[CH2:15]([C:18]1[C:31]2[C:22](=[CH:23][C:24]3[C:29]([CH:30]=2)=[C:28]([CH2:32][CH2:33][CH3:34])[C:27]([CH2:35][CH2:36][CH3:37])=[C:26]([CH2:38][CH2:39][CH3:40])[C:25]=3[CH2:41][CH2:42][CH3:43])[C:21]([CH2:44][CH2:45][CH3:46])=[C:20]([C:47]([O:49][CH3:50])=[O:48])[C:19]=1[C:51]([O:53][CH3:54])=[O:52])[CH2:16][CH3:17]
Reactant: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(c(CCC)c(C(=O)OC)c(C(=O)OC)c1CCC)C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CCCc1c(CCC)c(CCC)c2cc3c(CCC)c(C(=O)OC)c(C(=O)OC)c(CCC)c3cc2c1CCC
Yield: 90 %

Procedure:
Dimethyl 1,4,5,6,7,8-hexapropyl-9,10-dihydroanthracene-2,3-dicarboxylate obtained in REFERENCE EXAMPLE 1 was used. 2,3-Dichloro-5,6-dicyanobenzo-quinone (0.729 g, 3.21 mmols) was added to a solution of dimethyl 1,4,5,6,7,8-hexapropyl-9,10-dihydroanthracene-2,3-dicarboxylate (1.554 g, 2.832 mmols) in benzene (25 ml). Subsequently, the mixture was refluxed for an hour. After filtration, the solvent in the mixture was removed in vacuum. Hexane was added to disintegrate into powders, whereby 1.393 g of the title compound was obtained as a white solid. The isolation yield was 90%.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[O:18]=[S:19]1(=[O:29])[CH2:23][C:22]2[CH:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:21]=2[CH2:20]1>>[O:18]=[S:19]1(=[O:29])[CH2:23][C:22]2[CH:24]=[C:25]([NH:28][CH:4]=[C:5]3[C:16]4[C:8](=[CH:9][CH:10]=[C:11]5[C:15]=4[S:14][CH:13]=[N:12]5)[NH:7][C:6]3=[O:17])[CH:26]=[CH:27][C:21]=2[CH2:20]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc2c(c1)CS(=O)(=O)C2
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc2c(c1)CS(=O)(=O)C2
Yield: 37 %

Procedure:
The title compound was prepared in 37% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 2,2-dioxo-1,3-dihydrobenzo[c]thiophene-5-ylamine according to Procedure J: 1H NMR (DMSO-d6): δ 11.11 (d,1H), 10.89 (s, 1H), 9.27 (s, 1H), 8.06 (d, 1H), 7.82 (d, 1H), 7.47 (m, 2H), 7.13 (d, 1H), 6.98 (d, 1H), 6.5 (m, 2H); APCI−MS m/z 384 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[CH2:24]([OH:27])[CH2:25][OH:26]>>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[O:26][CH2:25][CH2:24][OH:27]
Reactant: OCCO
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: O=C1Nc2ccc(F)c3c(OCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (396 mg, 1.0 mmol) in ethylene glycol (Fisher Scientific, 60 mL) was added NaH (Aldrich, 95%, 2.0 g, 79.2 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated under reflux for 2 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were successively washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes) to give 6-fluoro-5-(2-hydroxy-ethoxy)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 127.0 mg, 40.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](Cl)[CH:7]=[C:6]2[CH3:14].[CH3:15][OH:16].C[O-].[Na+]>O>[CH3:15][O:16][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: CO
Reactant: COc1ccc2nc(Cl)cc(C)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2nc(OC)cc(C)c2c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A 1-liter, four-necked round bottom flask equipped with a mechanical stirrer, condenser, thermowatch and addition funnel was charged with 6-methoxy-4-methyl-2-chloroquinoline (3) (20.75 g, 0.1 moles) and methanol (250 ml). Methanolic sodium methoxide (25%, 108 g, 0.5 moles) was added over 15 minutes. The resulting mixture was heated to reflux and held for 24 hours. Additional methanolic sodium methoxide was added (25%, 42 g, 0.2 moles) and the reaction was refluxed an additional 21 hours. The mixture was cooled to 60° C. and water (200 ml) was added slowly. The slurry was cooled to 10° C., the product isolated by suction filtration, washed with water, and air dried. Yield was 17.9 g (88.2%); mp=58-59° C.; purity by HPLC=100 area %.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31]Br>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:31][CH2:30][O:29][CH3:28])[S:22]([CH3:25])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
8.9 g (25 mmol) of 6-benzyloxy-4-(methylsulfonyl)amino-2,2-dimethylchroman (Example 1e) were introduced in portions at 10° C. into a suspension of 0.54 g (30 mmol) of sodium hydride (60% dispersion) in 80 ml of DMA. After stirring at 50° C. for 30 min, 2.2 ml (22 mmol) of 2-methoxyethyl bromide were added dropwise at RT. The mixture was then heated to 110° C. for 1 h, concentrated in vac., the residue was treated with water and aqueous hydrochloric acid, the resinous product was taken up with EA, the solution was dried and concentrated, and the residue was chromatographed on silica gel using toluene/EA (3:1). 2.2 g of product were crystallized from appropriate fractions using petroleum ether, m.p. 66-68° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])(=[O:8])=[O:7])[CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cc1cccc(Br)c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(Br)c2)c(OC)c1
Reaction time: 1 h

Procedure:
While cooling with ice, 9.90 g of 3-bromobenzylsulfonyl chloride were initially charged in 120 ml of dichloromethane, and a solution of 11.55 ml of 2,4-dimethoxybenzylamine in 60 ml of dichloromethane was added dropwise within 15 minutes. The reaction mixture was allowed to come to room temperature and stirred for 1 hour. Subsequently, the mixture was washed with 50 ml of water, with 100 ml of 1 N aqueous hydrochloric acid, with 100 ml of saturated aqueous sodium hydrogencarbonate solution and finally once more with 100 ml of water. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue (14.30 g) was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][O:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][O:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)C(C)C
Yield: 32.8 %

Procedure:
1-(2-Aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.00 mL, 7.20 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372–376. The crude product was recrystallized from 93:7 acetonitrile:water and then from isopropanol (7.3 mL/g) and dried for two hours in a drying oven to provide 0.78 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 213–215° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH2:18][CH3:19])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)c1ccc(F)cc1
Yield: 90 %

Procedure:
To a cooled solution of 2-(4-fluorophenyl)-2-hydroxyacetic acid (5.0 g, 29.4 mmol) in ethanol was added con. H2SO4 (10 mL) over a period of 10 min. The reaction mixture was heated at reflux for 5 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (25 mL). The organic solution was washed with aqueous saturated NaHCO3 (25 mL×2), water (20 mL), brine solution (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-(4-fluorophenyl)-2-hydroxyacetate (5.0 g, 90%) as crude compound (oily liquid). The crude compound was taken to the next step without further purification. LC-MS (M+H2O)+=216. 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.46 (2H, m), 7.17-7.20 (2H, m), 6.11-6.13 (1H, m), 5.14 (1H, d, J=5.20 Hz), 3.35-4.13 (2H, m), 1.12-1.15 (3H, m).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].CCN(C(C)C)C(C)C>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2ccccn2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-pyridin-2-yl-ethylamine and DIEA to give 2-(2-pyridin-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 361 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH:33]=O)=[CH:23][CH:22]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH2:33][NH:1][CH:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=4[CH:17]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2c1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCCNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
6-(4-Amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 106 mg, 0.431 mmol) and 3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (100 mg, 0.431 mmol) were dissolved in N,N-dimethylformamide (2 ml), and the mixture to which sodium sulfate (400 mg) was added was stirred overnight at room temperature. The reaction solution was diluted with dichloromethane (12 ml), sodium triacetoxyborohydride (110 mg, 0.517 mmol) was added thereto and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added thereto, the organic layer was separated, washed sequentially with saturated sodium chloride solution, water (×3) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 193 mg (97%) of the title compound in the form of a light brown solid.
Reaction SMILES: ClCC1C=C(OC)C(CCl)=CC=1OCCC(C)CCCC(C)C.[Cl:24][CH2:25][C:26]1[CH:31]=[C:30](OC)[C:29](CCl)=[CH:28][C:27]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44][CH:45]([CH3:52])[CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:37]=1>O1CCOCC1>[Cl:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44][CH:45]([CH3:52])[CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:37]=1
Reactant: COc1cc(CCl)c(-c2cccc(OCCC(C)CCCC(C)C)c2)cc1CCl
Agent: COc1cc(CCl)c(OCCC(C)CCCC(C)C)cc1CCl
Solvent: C1COCCO1
Product: CC(C)CCCC(C)CCOc1cccc(-c2ccccc2CCl)c1

Procedure:
7.47 g (28.5 mmol) of 1,4-bis(chloromethyl)-2-(3,7-dimethyloctyloxy)-5-methoxybenzene (Ex. Z1), 6.22 g (17.1 mmol) of 2,5-bis(chloromethyl)4-methoxy-3′-(3,7-dimethyloctyloxy)biphenyl (Ex. E2) and 4.64 g (11.4 mmol) of 2,5-bis(chloromethyl-3′-(3,7-dimethyloctyloxy)biphenyl (Ex. Z3) in 3450 ml of dry 1,4-dioxane were polymerized at 98-100° C. analogously to