Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:24])[CH2:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:25]([N:27]1[C:39]2[CH:38]=[CH:37][C:36]([NH2:40])=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:24])[CH2:12][CH:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][C:15]([NH:40][C:36]2[CH:37]=[CH:38][C:39]3[N:27]([CH2:25][CH3:26])[C:28]4[C:33]([C:34]=3[CH:35]=2)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: N#Cc1ccc(NC(=O)CC(CC(=O)O)c2ccccc2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(CC(=O)Nc3ccc(C#N)c(Cl)c3)c3ccccc3)ccc21
Yield: 10 %

Procedure:
A solution of the compound obtained in Step 1 (1.2 g, 3.50 mmol), 9-ethyl-9H-carbazol-3-ylamine (0.736 g, 3.50 mmol), HATU (1.464 g, 3.85 mmol) and TEA (0.537 mL, 3.85 mmol) in DMF (10 mL) was stirred at room temperature for 3 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane), and crystallized from ethyl acetate to give the title compound (0.187 g, 0.350 mmol, 9.98%) as white crystals.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:8][C:7]=1[CH2:29][CH3:30])C.S(=O)(=O)(O)O.O>CO>[CH2:29]([C:7]1[CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([O:27][CH3:28])=[O:26])[C:18](=[CH:23][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:10]=[CH:11][C:6]=1[OH:5])[CH3:30]
Reactant: CCOCOc1ccc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)cc1CC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCc1cc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1O
Reaction time: 1 h

Procedure:
6.9 g (16.6 mmol) of dimethyl 4-[3-(4-ethoxymethoxy-3-ethylphenyl)propyl]phthalate are dissolved in 100 ml of methanol. 3 ml of concentrated sulphuric acid are added dropwise, and the medium is stirred fro 1 hour, and then poured into water, and extracted with dichloromethane. The organic phases are dried and concentrated. The residue obtained is purified by chromatography on a silica column (eluent heptane 80/ethyl acetate 20). A colorless oil is obtained (m=5 g, y=84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[N:13]([CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([O:23][CH2:24][C:25]1[C:26]([N:40]2[N:49]=[CH:48][C:47]3[C:42](=[C:43]([F:54])[CH:44]=[C:45]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:46]=3)[C:41]2=[O:55])=[N:27][CH:28]=[CH:29][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:22])[CH3:21].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:20]([O:23][CH2:24][C:25]1[C:26]([N:40]2[N:49]=[CH:48][C:47]3[C:42](=[C:43]([F:54])[CH:44]=[C:45]([C:50]([CH3:52])([CH3:51])[CH3:53])[CH:46]=3)[C:41]2=[O:55])=[N:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[N:13]([CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:22])[CH3:21]
Reactant: Cn1nc(Nc2cc(Br)cn(C)c2=O)cc1C1CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)n(C)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 26.4 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 126f (200 mg, 0.62 mmol), (2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 116c (268 mg, 0.65 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), sodium acetate (74 mg, 0.90 mmol), K3PO4 (191 mg, 0.90 mmol), and acetonitrile/water (5 mL/0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2.0 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 126g (100 mg, 26%) as a brown solid. MS-ESI: [M+H]+ 612.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[C:12]3[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:11]=23)[OH:9])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:24]>O=[Mn]=O>[Cl:24][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[C:12]3[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:11]=23)=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: ClC(Cl)Cl
Reactant: Cc1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Agent: O=[Mn]=O
Product: Cc1ncc(C(=O)c2ccc(F)c(Cl)c2)c2c1OC(C)(C)OC2

Procedure:
6.6 g of (4-fluorophenyl)(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanol was dissolved with heat in 150 mL of CHCl3. 12 g of MnO2 was added to this solution and the suspension was refluxed for 2 h. The MnO2 was then filtered over a 1 cm pad of silica gel and the clear organic phase evaporated to yield pure (3-Chloro-4-fluorophenyl) (2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanone.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10]2=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CN(C=O)C>[CH3:21][O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:20]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 2.34 g of NaH (80% suspension in mineral oil), 18.5 g of 1.5-diphenyl-4-imidazolin-2-one, 160 cc. of DMF, 18.5 g of 8-bromocaprylic acid methyl ester and 2.34 g of NaJ.
Reaction SMILES: [CH2:1]1[C@@H:11]2[C@H:5]([CH:6]=[CH:7][C:8]3[C:9]4[N:10]2[C:12]2[CH:21]=[CH:20][N:19]=[CH:18][C:13]=2[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH2:4][CH2:3][CH2:2]1.[I-].[K+].C(N(CC)CC)C.Cl[CH2:32][CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>CN(C=O)C>[CH2:1]1[CH:11]2[CH:5]([CH:6]=[CH:7][C:8]3[C:9]4[N:10]2[C:12]2[CH:21]=[CH:20][N:19]=[CH:18][C:13]=2[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH2:4][CH:3]([CH2:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:2]1
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Reactant: O=C(CCCl)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1)c1ccccc1
Temperature: 60 °C
Yield: 82.4 %

Procedure:
5.5 grams of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine, 3.6 grams of potassium iodide, 6.5 ml of triethylamine and 4.2 grams of β-chloropropiophenone were suspended in 100 ml DMF and heated to 60° C for 2 hours. The mixture was permitted to cool to room temperature, poured into 200 ml. of water and extracted with benzene. The benzene layer was washed with water, dried over potassium carbonate, filtered and evaporated to dryness in vacuo. The resulting oil was taken up in ether and converted to the hydrochloride salt as in Example 7, thus yielding 6.7 grams of the title compound, hydrochloride salt, m.p. 279° C (dec).
Reaction SMILES: C[O:2][C:3]1([O:34]C)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[C:17]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[C:23](=[O:27])[C:22]([O:30]C)([O:28]C)[C:21]5=[O:32])=[CH:16][S:15][CH:14]=3)[CH:9]=2)[C:4]1=[O:33].C(O)(=O)C.Br>O>[OH:30][C:22]1([OH:28])[C:21](=[O:32])[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([C:17]3[C:13]([C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[C:4](=[O:33])[C:3]([OH:34])([OH:2])[C:11]5=[O:12])=[CH:14][S:15][CH:16]=3)[CH:19]=2)[C:23]1=[O:27]
Reactant: COC1(OC)C(=O)c2ccc(-c3cscc3-c3ccc4c(c3)C(=O)C(OC)(OC)C4=O)cc2C1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(-c3cscc3-c3ccc4c(c3)C(=O)C(O)(O)C4=O)cc2C(=O)C1(O)O
Temperature: 110 °C
Yield: 43.2 %

Procedure:
3,4-bis(2,2-dimethoxy-1,3-dioxoindan-5-yl)thiophene (36) (178 mg, 0.361 mmol) was suspended in a solvent mixture of 2 ml of acetic acid and 2 ml of water, and the suspension was mixed with 2 ml of 47% hydrobromic acid. The mixture was refluxed at 110° C. for 1.5 hours. After it was cooled to room temperature, the reaction solution was diluted with water and then left all day and night to obtain a solid. The solid was filtered, washed with water, and dried, to obtain 68 mg (43%) of 3,4-bis(2,2-dihydroxy-1,3-dioxoindan-5-yl)thiophene (37) in the form of a beige solid. The readings for this compound are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([C:35]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[O:36])[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(c1cccc(Br)n1)N1CCCC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)N5CCCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (6-bromo-pyridin-2-yl)-pyrrolidin-1-yl-methanone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 133.1 %

Procedure:
5-Hydroxyindole (209 mg, 1.57 mmol) was dissolved in DMF (6 mL), and the solution was added with imidazole (132 mg, 1.93 mmol) and tert-butyldimethylsilyl chloride (333 mg, 2.21 mmol) at 0° C. followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution at 0° C. and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 5-(tert-butyldimethylsilyloxy)indole (517 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[NH:7][C:8](=[O:11])[NH:9][CH:10]=1)=[O:4].[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO>[F:19][C:14]1[CH:13]=[C:12]([CH:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:10][NH:9][C:8](=[O:11])[NH:7]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(=O)C1=CNC(=O)NC1c1ccc(F)c(F)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C1NC=C(C(=O)O)C(c2ccc(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (−)-4-(3,4-Difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (450 mg, 1.68 mmol) in 15 mL MeOH was added 1M NaOH (28 mL, 28.0 mmol). The solution was stirred under argon at room temperature for 6 h, poured 10% potassium hydrogen sulfate, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo to give the product. 1H NMR dH (DMSO) 9.17 (d, 1H, J=5.37Hz), 7.69 (s, 1H), 7.50-7.35 (m, 1H), 7.30-7.20 (m, 2H), 7.15-7.05 (m, 1H), 5.13 (d, 1H, J 2.44).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:14]S(C)(=O)=O)=[CH:8][C:7]=2[C:6]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=1)=[O:20].C(C1OC2C=CC([N+]([O-])=O)=CC=2C=1C(=O)C1C=CC(OCCCN(CCCC)CCCC)=CC=1)CCC.[H][H]>[Pt]=O>[CH2:4]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH2:14])=[CH:8][C:7]=2[C:6]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=1)[CH2:3][CH2:2][CH3:1]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Product: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1

Procedure:
A process for the preparation of dronedarone was reported in the above said patent EP 0 471 609, according to which process 2-(n-butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-nitrobenzofuran is reduced under pressure with hydrogen in the presence of platinum oxide as catalyst to form 2-(n-butyl)-3-(4-{3-[di(n-butyl)amino]propoxy}benzoyl)-5-aminobenzofuran (hereinafter Compound A), which is subsequently treated with methanesulfonyl chloride, in the presence of an acid acceptor, to give the desired compound. According to this process, dronedarone could be obtained with an overall yield of the order of 60%, starting from the 5-nitrobenzofuran derivative.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.N1C=CC=CC=1.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30](Cl)=[O:31])[CH2:24][CH2:25][CH3:26]>O1CCOCC1.CC(C)=O>[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30]([NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=[O:31])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCCCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)OCC)cc1

Procedure:
To a solution of 12.2 g. ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride in 40 ml dioxane and 40 ml acetone, there is added dropwise, after the addition of 8 ml pyridine, a solution of 12.3 g 2-butoxy-5-chlorobenzoyl chloride in 10 ml acetone. The reaction mixture is then stirred under reflux for 3 hours and thereafter evaporated in a vacuum. The residue is stirred with dilute hydrochloric acid and then with aqueous sodium bicarbonate solution, filtered with suction and washed with water. There are obtained 19 g of crude product which, after recrystallization from ethanol, with the addition of small amounts of water, gives ethyl 4-[2-(2-butoxy-5-chlorobenzamido)-ethyl]-phenylacetate; m.p. 80° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[O:16]1[CH2:20]CC[CH2:17]1.COCCl>C(OCC)(=O)C.O>[CH3:17][O:16][CH2:20][O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: C1CCOC1
Agent: COCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COCOCCN1CCCC1

Procedure:
To a mixture of 115 g of 1-(2-hydroxyethyl)-pyrrolidine, 106 g of triethylamine and 500 g of tetrahydrofuran at 0° C. was added 81 g of chloromethyl methyl ether. The temperature was raised from 0° C. to 20° C. over 10 hours whereupon 200 g of water was added to stop the reaction. Ethyl acetate was added to the reaction solution, which was allowed to separate. The organic layer was washed with water and concentrated in vacuum. Purification by vacuum distillation yielded 1-[2-(methoxymethoxy)ethyl]-pyrrolidine, designated [B-1].
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Br:16]Br>C(O)(=O)C>[Br:16][C:9]1[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]=2[S:11][CH:10]=1
Reactant: BrBr
Reactant: CCCn1c(SC)nc2ccsc2c1=O
Solvent: CC(=O)O
Product: CCCn1c(SC)nc2c(Br)csc2c1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution containing 1.01 g of the title compound of Step B dissolved in approximately 50 mL of acetic acid cooled to 0° C. was added 0.24 mL of bromine. The mixture was allowed to warm to room temperature and stirred for 24 h. The reaction mixture was filtered to obtain 0.60 g of a white solid. The white solid was purified by column chromatography on silica gel eluting with hexane and then 8:1 hexane:ethyl acetate. Collection and evaporation of those fractions containing the least polar component (according to thin layer chromatography, 6:1 hexane:ethyl acetate mixture as the development solvent) yielded 0.12 g of the title compound of Step C, a compound of the invention, as a white solid melting at 146-147° C. 1H NMR (400 MHz, CDCI3): δ 1.02 (t,3H), 1.81 (m,2H), 2.71 (s,3H), 4.11 (t,2H), 7.69 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1[OH:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:17][C:9]3[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1O)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1cccc2nc(-c3cccc(Cl)c3)oc12
Temperature: 190 °C
Yield: 102.7 %

Procedure:
A stirred suspension of N-(3-chlorobenzoyl)-2-hydroxy-3-nitroaniline (4.5 g, 0.0117 mol), p-toluenesulfonic acid (0.30 g) and 50 ml of diphenyl ether were heated at 190° C. for 1 hour. The dark reaction mixture was dissolved in 100 ml CH2Cl2 and washed with saturated sodium bicarbonate and then water. The CH2Cl2 was evaporated and hexane was added, causing a brown solid to separate. The dark solid was filtered, dissolved in 75% CH2Cl2 in hexane and washed onto a silica gel column. Elution with this solvent, gave 3.3 g of the title compound. This material could be recrystallized from methanol to give 2-(3-chlorophenyl)-7-nitrobenzoxazole although it was pure enough from the chromatography to use for the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCOCCCCCCBr
Reactant: NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(C#CCCOCCCCCCBr)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
A mixture of 3-bromo-benzenesulfonamide (625 g), 6-bromohexyl but-3-ynyl ether (850.1 g), bis(triphenylphosphine)palladium (II) chloride (62.5 g), triphenylphosphine (18.1 g) and triethylamine (536.3 g) in tetrahydrofuran (6250 ml) was stirred under an atmosphere of nitrogen for 20 mins. Copper (I) iodide (12.5 g) was then added to give a dark red/brown mixture that was heated to 50° C. for 23 h. The reaction mixture was then cooled to room temperature and filtered through a short silica pad (100 g). The pad was washed with additional tetrahydrofuran (15.6 L) and the resulting solution then concentrated under reduced pressure to give crude product (1382 g) as a viscous oil. This was purified by chromatography (7 kg silica) eluting with 5:1 petroleum ether:ethyl acetate followed by 2:1 petroleum ether:ethyl acetate to give the title compound (932.9 g) as an oil, LC RT=5.69 min, δ (DMSO-d6) 7.79 (1H, s), 7.76 (1H, d, J 7.6 Hz), 7.56 (2H, m), 7.42 (2H, m), 3.55 (2H, t, J 6.6 Hz), 3.49 (2H, t, J 6.6 Hz), 3.42 (2H, t, J 6.6 Hz), 2.68 (2H, t, J 6.6 Hz), 1.76 (2H, m), 1.50 (2H, m), 1.35 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:20][CH2:21]2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc(Cl)c1O

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (20 mg, 0.055 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 1.0 mmol) followed by formation of the dihydrochloride salt to afford the desired product (18 mg, 59%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.49 (d, J=8.9 Hz, 1H), 8.32 (d, J=9.1 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 5.80-5.70 (m, 1H), 4.03 (s, 3H), 3.08 (d, J=6.6 Hz, 2H), 2.93 (s, 6H), 2.76 (s, 3H), 2.49-2.39 (m, 2H), 2.08-1.96 (m, 3H), 1.72-1.62 (m, 2H), 1.47-1.35 (m, 2H). ESI MS m/z 483 [M+H]+; HPLC>99% (AUC), tR=9.62 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN1CCCC1=O>[O:24]1[CH2:25][CH2:26][N:21]([C:11]2[C:10]([CH3:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH:14]3[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:22][CH2:23]1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: Cc1c(N2CCOCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 150 °C
Reaction time: 3 h
Yield: 2.2 %

Procedure:
6,7-Difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) is suspended in N-methylpyrrolidone (5 ml) and thereto is added morpholine (1.82 g), and the mixture is stirred at 150° C. for 3 hours. After the reaction, the reaction mixture is concentrated, and the resulting residue is recrystallized from ethanol to give 7-morpholino-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.05 g), as pale yellow flakes, m.p. 227.5°-228° C.