Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[N:17]=1)=[O:11]>CCO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[N:17]=1)=[O:11]
Reactant: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc(N)c2)cs1
Yield: 72.2 %

Procedure:
A suspension of compound 14 (0.391 g, 1 mmol) and Pd/C (10 wt. %, 50 mg) in EtOH and AcOH (20 ml+1 ml) was reacted under hydrogen atmosphere at 50° C. for 2 hours. The catalyst was removed by filtration through a pad of Celite. After removal of the solvent in vacuo, the crude material was dissolved in EtOAc and washed with NaHCO3 solution and brine and dried over Na2SO4. The solvent was removed by rotary evaporation. The crude solid was purified by flash chromatography (EtOAc/hexane, 2:1) to give compound 20 (0.261 g, 72.4%). 1H NMR (300 MHz, CDCl3) δ 11.2 (1H, s), 7.22 (1H, s), 7.20 (1H, s), 7.16 (1H, brs), 7.10 (1H, s), 6.70-6.66 (1H, m), 3.69 (3H, s), 2.28 (2H, t, J=7.4 Hz), 2.06 (2H, dd, J=7.3, 4.7 Hz), 1.61-1.45 (4H, m), 1.22-1.08 (4H, m). 13C NMR (75 MHz, CDCl3) δ 174.6, 171.8, 159.6, 150.1, 147.3, 135.7, 130.2, 116.9, 115.3, 113.0, 108.1, 51.9, 36.1, 34.3, 29.07, 29.01, 25.09, 25.00, 21.4.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[N:32]2[N:33]=[C:34]([SH:36])[N:35]=[C:31]2[N:30]=[CH:29][CH:28]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:36][C:34]3[N:35]=[C:31]4[N:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]4[N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cc1ccnc2nc(S)nn12
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4nccc(C)n4n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 7-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) d 1.53-1.73 (m, 8H) 2.14 (m, 1H) 2.24 (m, 1H) 2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.62 (m, 1H) 2.80 (d, J=17.9 Hz, 1H) 2.96 (d, J=20.0 Hz, 1H) 3.80 (s, 3H) 7.03 (d, J=8.2 Hz, 1H) 7.15 (d, J=4.7 Hz, 1H) 7.22 (dd, J=8.4, 2.06 Hz, 1H) 7.29 (d, J=1.9 Hz, 1H) 8.63 (d, J=4.7 Hz, 1H). MS (APCI) calcd for C25H27ClN4O4S; 515.03; found M=515.0.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:30]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:40][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was coupled to L-phenylalanine benzyl ester toluenesulfonic acid salt using the procedure described in Method 3 to give the title compound as an oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13]C=1)([CH3:3])[CH3:2].ClC1C=CC([N+]([O-])=O)=C[N:20]=1>>[CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[N:20]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cn1

Procedure:
This compound is prepared according to the same procedure as described for Intermediate 7 using 2-chloro-5-nitropyridine.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16](Cl)(=[O:20])[C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[CH3:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]2=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]3[C:16](=[O:20])[C:17]2=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c2ccccc2cc2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1c2ccccc2c2c3c(cccc13)C(=O)C2=O
Reaction time: 2 h

Procedure:
To a cold (−10° C., brine/ice cooling bath) stirred mixture of 5.43 g (28.2 mmol) of 9-methylanthracene and oxalyl chloride (13.50 mL, 159.5 mmol) in CS2 (60 mL) was added aluminium chloride (6.0 g, 45 mmol). The solution changed from a red-orange colour to a very intense dark crimson colour and vigorous effervescence was observed (hydrogen chloride) and an exotherm occurred raising the reaction temperature from −10° C. to −4° C. After a few minutes stirring the exotherm eased off and an intense dark red tar deposited from the solution which lightened to a yellow colour, the reaction mixture was then stirred cold for a period of 2 hours. After 2 hours, additional CS2 (60 mL) and aluminium chloride (4.5 g, 33.7 mmol) were added, and stirring was continued for 2 hours at 0° C. and then overnight at room temperature. HCl (2M, aq, 150 mL) was then added to the reaction mixture [NOTE: Extreme caution, very exothermic reaction ensues that causes vigorous reflux of reaction solvent], the reaction mixture was then stirred vigorously for 2 hours (large egg-shaped magnetic stirrer follower stirred at 1250 rpm) to decompose the dark red tar to an orange precipitate which was then collected by filtration, washed with water (2×150 mL), and then digested well with 300 mL of 5% NaOH(aq) for a period of 1 hour. The insoluble solids were collected by filtration, washed with water (2×50 mL), and dried in vacuo in a vacuum oven (oil immersion pump) to constant mass (22 hours). Yield: 2.411 g (34.7%, pale orange powder).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]4)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CC1CCC(Nc2ncc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCC(Nc2ncc(Cc3c[nH]c4ncc(Cl)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine (64, 0.120 g, 0.242 mmol) in 5.0 mL of tetrahydrofuran, tetrabutylammonium fluoride trihydrate (0.20 g, 0.63 mmol) is added. The reaction is stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are collected and concentrated under vacuum to provide the desired compound (P-3009, 1.4 mg). MS (ESI) [M+H+]+=355.95.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NCC(O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 14, 1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester, according to the procedure of Example 1 as an off-white solid; mp 74-83° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.10-1.20 (m, 6H), 1.20-1.90 (m, 8H), 2.60-3.40 (m, 6H), 3.80-4.10 (m, 6H), 4.85-4.95 (m, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.84 (t, 2H), 7.00 (d, 2H), 7.57 (d, 2H), 10.57 (br s, 1H), 10.70 (br s, 1H); MS (ES) m/z: 602.1 (MH+); HRMS Calcd. for C29H40N5O7S (MH+): 602.2634. Found: 602.2642.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:35]([O:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH2:16][CH2:17]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1)(=[O:37])[CH3:36]
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Reaction time: 1 h
Yield: 92 %

Procedure:
Dissolve 0.5 g (1.07 mmol) of the compound obtained in Example 1 at 0° C. in 0.255 ml (2.7 mmol) of acetic anhydride under an inert atmosphere. Add 2 volumes of pyridine (0.5 10 ml) and continue stirring while returning to room temperature for a period of 1 h 30. Neutralise with a saturated sodium hydrogen carbonate solution. After extraction with ether (2×25 ml), the product is purified by chromatography on a silica column (eluant:ethyl acetate/petroleum ether, 20:80) and obtained in pure form as a solid in a yield of 92%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[CH2:11]([O:10][C:8]([C:3]1[C:2]([O:1][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccnc1C(=O)OCC
Yield: 82.3 %

Procedure:
To a stirred solution of 2.0 g (12 mmol) of the title compound from Step A in 50 mL of acetone under an atmosphere of nitrogen was added 2.5 g (18 mmol) of potassium carbonate and 2.4 g (14 mmol) of ethyl bromoacetate. The reaction mixture was refluxed overnight. After cooling, the inorganic materials were filtered off and washed with acetone. The filtration was concentrated and purified by MPLC (Biotage Horizone: Flash 65i) eluent: 100% dichloromethane to 12% methanol in dichloromethane to give 2.5 g of the title compound as an oil. LC/MS: (M+1) 240.9
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12]C(=O)OC(C)(C)C)[CH2:5]2.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH2:12])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CNc2ccc(Br)cc2C1
Reaction time: 3 h
Yield: 220.2 %

Procedure:
To a solution of (6-Bromo-1,2,3,4-tetrahydro-3-quinolinyl)carbamic acid, 1,1-dimethylethyl ester (652 mg, 2 mmol) in dichloromethane at RT under argon was added trifluoroacetic acid (1 mL). After 3 hours, the mixture was concentrated. Chloroform (10 mL) was added and concentrated again in vacuo to afford the title compound (1 g), an oil, which was used without further purification. MS; M(+H)+=227.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25].Cl>CN(C=O)C.O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH:24]=[CH2:23])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)c2[nH]c(=O)ccc12
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(OC(C)=O)c2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 Grams of 5-acetoxy-8-hydroxy-2(1H)-quinolinone was dissolved in 100 ml of DMF, to this solution was added 14 g of potassium carbonate and 9 ml of allyl bromide, stirred at room temperature for 8 hours. Under ice-cooling and stirring conditions, the reaction mixture was acidified by adding hydrochloric acid, this mixture was diluted by adding 200 ml of water. The mixture was extracted with 500 ml of ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure. The residue thus obtained was recrystallized from a mixed solvent of ethyl acetate-n-hexane, there was obtained 9.8 g of 5-acetoxy-8-allyloxy-2(1H)-quinolinone as pale yellow needle-like crystals.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[C:14]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:12][C:11]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(-c2ccccc2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 2-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(0) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.175 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Cl-].[Na+].O.O>N1C=CC=CC=1>[O:8]=[C:6]1[NH:5][CH2:4][C@H:3]([CH2:2][O:1][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[O:7]1
Reactant: O=C1NC[C@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CNC(=O)O2)cc1
Reaction time: 2 h

Procedure:
A solution of (5R)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (10.0 g), prepared as described in Tetrahedron: Asymmetry 1995, 6, 1181-1190, in pyridine (60 mL) at −10° C. was treated with para-toluenesulfonyl chloride (21.2 g), stirred for 2 hours, poured into 1:1 brine/water (100 mL), and extracted with ethyl acetate. The extract was washed with 1:1 saturated sodium bicarbonate/water and 1:1 brine/water, and the washes were back extracted with ethyl acetate. The combined extracts was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 272 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 2H), 7.39 (d, 2H), 4.80 (m, 1H), 4.18 (d, 2H), 3.70 (t, 1H), 3.50 (dd, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25](Cl)[C:24]=2[N:23]=[CH:22]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[CH2:1]([NH:8][C:25]1[C:24]2[N:23]=[CH:22][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c(Cl)nc3ccccc3c21
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
2 ml of benzylamine was added to 70 mg (0.187 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-4-chloro-1H-imidazo-[4,5-c]quinoline. The resulting mixture was heated at 150° C. and stirred for 3 hours. An excess amount of benzylamine was distilled off under reduced pressure and 1N hydrochloric acid and brine were added thereto. The resulting solution was extracted twice with methylene chloride. The organic phase was washed with a saturated sodium hydrogencarbonate aqueous solution and dried (Na2SO4). The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=150:1 (v/v)) to obtain 79 mg (0.177 mmol) of 4-benzylamino-1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline shown below as white powder (mp: 151 to 153.5° C.). ##STR46## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3380, 3310, 2930, 1680, 1595, 1540, 1245, 1160.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([CH3:16])=[CH:6][N:5]2[C:17]=1[C:18]([O:20]CC)=[O:19].[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([CH3:16])=[CH:6][N:5]2[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2c(OCCC(C)C)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCC(C)C)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C

Procedure:
2.25 g (7.4 mmol) of ethyl 2,6-dimethyl-8-(3-methylbutoxy)imidazo[1,2-a]pyridine-3-carboxylate Example 251A were initially charged in 157 ml of THF/methanol 5:1, 37 ml (37 mmol) of 1 N lithium hydroxide solution were added and the reaction mixture stirred at RT over the weekend. The mixture was then cooled to 0° C., acidified to pH 4 with 6 N hydrochloric acid and freed from the organic solvent under reduced pressure. The precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 1.64 g (80% of theory; purity 100%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Li+]>O1CCCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([CH2:26][OH:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](CO)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.9 %

Procedure:
To a solution of methyl(2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 13, 350 mg, 0.580 mmol) in Tetrahydrofuran (THF) (7 ml) at 0° C. lithium borohydride (0.568 ml, 1.160 mmol) was added and the reaction mixture was stirred at room temperature and under nitrogen atmosphere for 3 days. Volatiles were evaporated in vacuo and the residue was dissolved in Methanol (2 ml)/HCl 1 N in water (3 ml). After 1 h stirring combined solvents were evaporated in vacuo. The residue was dissolved in Ethyl acetate (4 ml) and washed with NaHCO3 sat. sol. (2×3 ml). Organic phase was dried and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 10 g as column and Dichloromethane/Methanol 98:2 as eluent affording the title compound (110 mg, 0.191 mmol, y=33.0%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[N:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[N:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Nc1ccc(Cl)nn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nn3)cccc12
Yield: 32.5 %

Procedure:
A solution of 5-dimethylamino-1-naphthalenesulphonyl chloride (3.98 g), 3-amino-6-chloropyridazine (1.91 g) and 4-dimethylaminopyridine (100 mg) in pyridine (25 ml) was heated at 85° C for 18 hours. Volatile material was removed by evaporation and dichloromethane (50 ml) was added. Insoluble material was removed by filtration and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), and the resulting foam was crystallised from ether to give 5-(dimethylamino)-N-(6-chloro-3-pyridazinyl)-1-naphthalenesulphonamide (1.74 g), m.p. 153°-154° C.; mass spectrum (positive chemical ionisation ((+)ve CI)): 363 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.4 %

Procedure:
In the case of compound 11, the required intermediate for step a) was synthesised as follows: To a stirred solution of 4-bromo-1-methyl-2-trifluoromethylbenzene (10 g) in tetrachloromethane (100 ml) at room temperature is added N-bromosuccinimide (7.5 g) and azobisisobutyronitrile (700 mg). After 15 h of stirring at reflux, the reaction is allowed to cool to room temperature, water is added and the reaction mixture is extracted twice with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (9:1 cyclohexane:ethyl acetate) to yield 4-bromo-1-bromomethyl-2-trifluoromethylbenzene (7.1 g).