Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C1COCC1.[Li]CCCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([CH3:39])[C:19]=1[CH3:40]>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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]>[CH3:39][C:20]1[C:19]([CH3:40])=[C:18]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)[S:22][C:21]=1[C:23]1[N:27]2[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:26]2=[N:25][C:24]=1[CH3:38]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(C)c3C)c(C)nc12
Reactant: Cn1cncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)c(C)c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a −78° C. solution of 1-methyl-1,2,4-triazole (0.056 mL, 0.74 mmol) and THF (2 mL) is added a 1.6 M solution of n-BuLi in hexanes (0.46 mL, 0.74 mmol). The solution is warmed to ambient temperature and stirred for 30 minutes. The solution is cooled to 0° C., a 0.5 M solution of ZnCl2 in THF (4.70 mL, 2.33 mmol) is added and the solution warmed to ambient temperature and stirred for 30 minute. 3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.25 mmol) and PdCl2(dppf) (0.009 g, 0.012 mmol) is added and the solution heated at 65° C. overnight, diluted with EtOAc (25 mL), washed with sat. NH4Cl (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-60% EtOAc/hexane gradient), followed by a second purification by ISCO column chromatography (100% Et2O) furnish the title compound (0.07 g, 0.17 mmol, 70%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.06 (s, 3H), 2.29 (s, 3H), 2.47 (s, 3H), 2.51 (s, 3H), 3.27-3.37 (m, 1H), 3.97 (s, 3H), 6.69 (s, 1H), 8.00 (s, 1H). LC/MS (m/z): calcd. for C22H28N6S (M+H)+: 409.6; found: 409.2.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].C([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=2)[CH:28]=[N:27]1)(OC(C)(C)C)=O>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[CH:33]=2)[CH:28]=[N:27]1
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc2cn[nH]c2c1
Temperature: 100 °C
Yield: 5.6 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 280 mg of 1-Boc-6-aminoindazole in place of the 3-(tert-butyl)aniline. The reaction mixture is concentrated under reduced pressure and taken up in 13 ml of 1,4-dioxane and 3 ml of 1N hydrochloric acid, and is then microwave-heated for 10 minutes at 100° C. After cooling to ambient temperature, the reaction mixture is concentrated under reduced pressure and taken up in 30 ml of water, and then a saturated aqueous solution of sodium bicarbonate is added so as to obtain a pH in the region of 8. The precipitate formed is filtered off and washed with water, ethyl acetate and ethyl ether. After purification by silica column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 70/30 in dichloromethane of 0% to 100%, 20 mg of N-(1H-indazol-6-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:6][N:5]=1)(=[O:3])[NH2:2].[Li+].[OH-]>C1COCC1.O>[C:1]([C:4]1[S:8][C:7]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(N)=O)s3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nnc(C(N)=O)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution ethyl 2-(6-(5-carbamoyl-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.448 mmol) in THF (3 mL) was added a solution of LiOH (2.24 mmol) in water (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours then concentrated in vacuo. The residue was purified by preparative HPLC then lyophilized to give 2-(6-(5-carbamoyl-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid as an off white solid (17%). 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.31 (s, 1H), 8.44 (s, 1H), 8.07 (s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 5.54 (dd, 1H), 3.07 (dd, 1H), 2.32 (s, 3H), 2.18 (dd, 1H). MS (ESI) m/z: 348.1 [M−1]−.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[NH:4][CH:5]([CH3:7])[CH3:6].N[C:14](N)=[O:15]>O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]2[N:4]([CH:5]([CH3:7])[CH3:6])[C:14](=[O:15])[NH:1][C:2]=2[CH:11]=1
Reactant: NC(N)=O
Reactant: CC(C)Nc1ccc(Cl)cc1N
Solvent: O
Product: CC(C)n1c(=O)[nH]c2cc(Cl)ccc21
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 43.8 %

Procedure:
A mixture of 2-amino-4-chloro-N-isopropylaniline (14 g) and urea (15 g) was stirred at 160° C. for 3.5 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, an aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. To the residue was added isopropyl alcohol and the obtained crystal was separated by filtration and recrystallized from acetonitrile to give 5-chloro-1-isopropylbenzimidazol-2-one (7 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17]([O:19]CC)=[O:18])[C:9](=[O:16])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:5])C.[OH-].[Na+].Cl>CO>[C:6]1([C:4]([OH:5])=[O:3])[CH:7]=[C:8]([C:17]([OH:19])=[O:18])[C:9](=[O:16])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CCOC(=O)c1cc(C(=O)OCC)c2ccccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(C(=O)O)c2ccccn2c1=O
Temperature: 0 °C
Yield: 28 %

Procedure:
To a solution of 1,3-diethoxycarbonyl-4H-quinolizin-4-one (896 mg) in methanol (9 ml) was added 6N aqueous sodium hydroxide (2.58 ml) at room temperature and the mixture was heated with reflux for an hour. After cooling to 0° C., the reaction mixture was acidified to pH 2 with 6N hydrochloric acid and the precipitate was filtered and washed with water to give 4H-quinolizin-4-one-1,3-dicarboxylic acid (202 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[S:22][C:21]=3[CH:32]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:18]=[CH:19][C:20]2[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])[S:22][C:21]=2[CH:32]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:35])([CH3:36])[CH3:1])=[C:7]([CH3:33])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)NCC(=O)O)sc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)NCC(=O)O)sc2c1
Yield: 79.2 %

Procedure:
[(6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carbonyl)-amino]-acetic acid (220 mg, 0.432 mmol) is reduced by NaBH4 (33 mg, 0.863 mmol) as in Step F11 to afford the title compound (175 mg, 79%).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:35])=[O:34]
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1c2c(ccc3c2ccn3S(=O)(=O)c2ccc(Cl)cc2Cl)OCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,4-dichlorobenzenesulfonyl chloride (28 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,4-dichlorophenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (2 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (0.7 mg). MS m/z 412 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[S:20][C:19]([CH:21]([CH3:23])[CH3:22])=[N:18][C:17]=1[CH3:24])=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:23][CH:21]([C:19]1[S:20][C:16]([CH2:14][OH:13])=[C:17]([CH3:24])[N:18]=1)[CH3:22]
Reactant: CCOC(=O)c1sc(C(C)C)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1nc(C(C)C)sc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
Diisobutylaluminum hydride (1.5M in toluene; 6.5 mL, 9.8 mmol) was added dropwise to a solution of 2-(1-methylethyl)-4-methylthiazole-5-carboxylic acid ethyl ester (Example 9; 1.0 g, 4.7 mmol) in toluene (8 mL) at −75° C. After 15 min, the cold reaction mixture was treated with saturated aqueous potassium sodium tartrate (15 mL) and the reaction mixture was allowed to warm to room temperature. The reaction mixture was filtered and the solids were washed thoroughly with toluene. The combined filtrates were washed with brine (50 mL) and the brine layer was back-washed with toluene (3×35 mL) and ethyl acetate (2×35 mL) to extract the product completely. The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give 2-(1-methylethyl)-4-methylthiazole-5-methanol (742 mg, 92% yield).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N)#N.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]1=[O:38]>>[CH2:10]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:12]1=[O:38])[C:3]1[CH:4]=[CH:5][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(N)c1
Reactant: CN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Product: N#Cc1cccc(Nc2nccc(N3CCN(Cc4ccccc4)C(=O)C3c3ccccc3)n2)c1
Yield: 58 %

Procedure:
Intermediate 5, (0.39 g, 1.03 mmol) and 3-cyanoaniline (0.14 g, 1.17 mmol) were reacted together following the procedure detailed for the compound of Example 2, which gave the title compound as a pale yellow solid (0.28 g, 58%).
Reaction SMILES: S1C2C3C=CC=NC=3C=CC=2C=CN1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].[S-:24][C:25]#[N:26].[K+].BrBr>>[NH2:26][C:25]1[S:24][C:17]2[C:16]([Cl:15])=[C:22]([F:23])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: C1=Cc2ccc3ncccc3c2SN1
Agent: [K+]
Product: Nc1nc2ccc(F)c(Cl)c2s1

Procedure:
Pyrido-benzothiazine compounds having anti-microbial activity are prepared by (a) reacting 3-chloro-4-fluoroaniline with potassium thiocyanate and bromine to produce 2-amino-6-fluoro-7-chlorobenzothiazole, (b) reacting 2-amino-6-fluoro-7-chlorobenzothiazole with sodium hydroxide to produce the disulfide of 2-amino-5-fluoro 6-chlorothiophenol, (c) reacting the disulfide with sodium monochloroacetate to produce 7-fluoro-8-chloro-2H-1,4-benzothiazin-3(4H)-one, (d) reducing 7-fluoro-8-chloro-2H-1,4-benzothiazin-3(4H)-one to produce 7-fluoro-8-chloro-3,4-dihydro-2H-1,4-benzothiazone, (e) reacting 7-fluoro-8-chloro-3,4-dihydro-2-H-1,4-benzothiazone with ethyl ethoxymethylenemalonate and cyclyzing the intermediate formed with polyphosphoric acid to produce ethyl 9-fluoro-10-chloro-7-oxo-2,3-dihydro-7H-pyrido[1,2,3 de] [1,4]-benzothiazine-6-carboxylate and (f) hydrolyizing the ethyl carboxylate to produce the corresponding carboxylic acid.
Reaction SMILES: [C:1]12([C:8]3[C:12](=C)[CH:11]=[CH:10][CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)C>O1CCCC1>[C:1]12([C:8]3[CH2:12][CH:11]=[CH:10][CH:9]=3)[CH2:7][CH:4]([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: C=C1C=CC=C1C12CCC(CC1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C1=CCC(C23CCC(CC2)C3)=C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of norbornylfulvene (14.37 g, 90.8 mmol) dissolved in 100 mL tetrahydrofuran was cooled to 0° C. before LiAlH4 (5.00 g, 132 mmol) was added over 2 minutes. After stirring at room temperature for 17 hours, the reaction was cooled to 0° C. and 100 mL water were added dropwise over 1 hour. Then, 200 mL water/50 mL concentrated aqueous HCl and 100 mL diethyl ether were added. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (3×50 mL). The organic layers were dried over MgSO4, filtered, and rotavapped to provide the crude product as a light yellow oil in quantitative yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7]C=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.CS(O[CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:35](=[O:49])[NH:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:48])[N:44]2[CH3:47])=[CH:39][CH:38]=1)(=O)=O>O>[ClH:34].[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([C:35]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:48])[N:44]3[CH3:47])=[CH:39][CH:38]=2)=[O:49])=[C:28]([NH:27][CH2:26][CH2:25][N:5]2[CH2:6][CH2:7][CH:3]([F:2])[CH2:4]2)[CH:33]=1
Reactant: Fc1cccnc1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCOS(C)(=O)=O)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCN3CCC(F)C3)cc21
Temperature: 40 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
3-Fluoropyridine hydrochloride (240 mg) and sodium carbonate (250 mg) were added to a dimethylformamide solution of 2-({5-chloro-2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamoyl]phenyl}amino)ethyl methanesulfonate (595 mg), followed by stirring at 40° C. for 15 hours. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was dried with magnesium sulfate and then the solution was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, chloroform:methanol, 1:0 to 95:5). By treating the resulting free base with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-2-{[2-(3-fluoropyrrolidin-1-yl)ethyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide hydrochloride (156 mg) was obtained as a solid.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(OCCCN2CCC(O)CC2)c1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1cccc(OCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(3-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[3-(3-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24][CH3:25])=[O:23].O>CO.[OH-].[Na+]>[OH:3][CH:4]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Yield: 83.7 %

Procedure:
0.227 g of sodium borohydride was added portionwise over approximately 30 minutes at a temperature of less than 30° C., with stirring and under an inert atmosphere, to a mixture of 2.5 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate in 40 cm3 of methanol to which had been added one drop of 5N aqueous sodium hydroxide solution. After stirring the reaction mixture for 3 hours at a temperature in the region of 20° C., 100 cm3 of water were added and then the mixture was extracted with 4 times 50 cm3 of ethyl acetate. The combined extracts were washed with 3 times 50 cm3 of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residual oil obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 3.2 cm; silica volume 100 cm3), elution was carried out with pure ethyl acetate, and 25-cm3 fractions were collected. The fractions comprising the expected product were combined and then concentrated as above. 2.1 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate were obtained in the form of an oil with a pale yellow color. The hydrochloride was prepared in the following way: a solution of 0.5 g of the oil obtained above, dissolved in 15 cm3 of dichloromethane, was poured with stirring into 4 cm3 of a 1N solution of hydrochloric acid in diethyl ether. A product precipitated and then crystallized by addition of 25 cm3 of diethyl ether. The solid was filtered off, washed with 2 times 10 cm3 of ether, and dried under vacuum over potassium hydroxide (5 kPa) and then, to constant weight, in an oven under reduced pressure (10 Pa) at a temperature in the region of 40° C. 0.35 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetate dihydrochloride was obtained in the form of a solid with an off-white color.
Reaction SMILES: ClC1C=CC(C[CH:9]([C:17]([CH:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Cl)=[CH:30]C=2)[S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)SC2C=CC=CC=2)=CC=1.[Cl:35]C1C=CC=CC=1>>[Cl:35][C:24]1[CH:23]=[CH:22][C:21]2[S:20][C:19]([C:27]3[CH:28]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:17]([CH3:9])[C:26]=2[CH:25]=1
Reactant: O=C(C(Cc1ccc(Cl)cc1)Sc1ccccc1)C(Cc1ccc(Cl)cc1)Sc1ccccc1
Reactant: Clc1ccccc1
Product: Cc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
55.7 parts by weight of p-chlorophenylthiophenylmethylmethyl ketone and 500 parts by weight polyphosphoric acid are combined in a stoppered flask and heated with stirring for 3.5 hours at 180° C. 350 Parts by volume of chlorobenzene is added to the reaction mixture and the resulting solution is heated at reflux temperature for an additional hour. After cooling the organic phase of this reaction solution is decanted off; the inorganic phase is dissolved in ice water and extracted once each with benzene and ethyl ether. The combined organic phases are then washed once with a saturated solution of sodium bicarbonate, washed once with brine, and dried over magnesium sulfate. Concentration of this solution in vacuo affords a dark solid. Crystallization of this solid (2xs) from heptane affords a brown solid. Sublimation at 135° C/0.1mm of this brown solid affords 5-chloro-3-methyl-2-phenylbenzo[b]thiophene, melting at 108.5°-110° C. This compound is represented by the following structural formula. ##STR10##
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1cccc(-c2cc3ncccc3c(Cl)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cc3ncccc3c(Cl)n2)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 5-chloro-7-(3-methoxyphenyl)-[1,6]naphthyridine (0.052 g, 0.2 mmol) in dichloromethane (2 mL) was added boron tribromide (1 M solution in dichloromethane, 0.4 mL, 0.4 mmol) at −78° C. The resulting mixture was slowly warmed to room temperature. The residue was quenched with water and neutralized with aqueous sodium carbonate. The aqueous solution was then extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a tan oil. Purification by flash chromatography eluting with hexanes/EtOAc (1:1) afforded the title compound as a yellowish solid (0.040 g). 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (b, 1H), 9.19 (dd, 1H), 8.54-8.64 (m, 1H), 8.37 (s, 1H), 7.77 (dd, 1H), 7.64 (m, 2H), 7.32 (t, 1H), 6.87 (m, 1H); MS (m/e) calculated for C16H13ClN2O 256, found 257.5 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1>[Ni].CO>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)cc1
Yield: 99.6 %

Procedure:
4-Nitrodiphenyl ether (3.92 g, 18 mmol) was hydrogenated over Raney nickel (1.5 g) in methanol (100 mL) at 25° C. at 50 psi for 2 hours. The reaction mixture was celite filtered, and the volatiles were stripped rigourously under reduced pressure to give 4-phenoxyaniline (3.32 g, 97.6%) as an off-white solid.