Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.[OH-].[K+].I[CH3:24]>CC(C)=O.O>[CH3:24][O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.2 g (0.75 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide in 2 mL of acetone cooled to 0° C. was added a solution of 0.065 g (1.16 mmol) of potassium hydroxide in 1 mL of water followed by 0.164 g (1.16 mmol) of iodomethane. The resulting mixture was stirred at room temperature overnight then 10 mL of water was added. The mixture was extracted with ether and the organic layer was washed with water and brine, then dried by sodium sulphate and filtered. The solvent was removed by evaporation under reduced pressure and the residue chromatographed on silica gel with a 3% methanol-dichloromethane mixture. Chromatographically homogenous fractions were pooled, the solvents were removed under reduced pressure and the residue was crystallised from toluene to give the product as off-white crystals of m.p. 157.9°-159.4° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[CH:7]=[CH:6][CH:5]=3)[O:12][N:11]=2)[CH:14]=1
Reactant: Brc1cccc(-c2nc(-c3cccnc3)no2)c1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCCN1c1cccc(-c2nc(-c3cccnc3)no2)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of the product of Example 63 (200 mg, 0.66 mmol) and pyrrolidin-2-one (Aldrich, 85 mg, 0.99 mmol) in toluene (anhydrous 10 mL) was degassed and purged with nitrogen three times, cesium carbonate (Aldrich, 324 mg, 0.993 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Aldrich, 12.1 mg, 0.013 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Aldrich, 23.0 mg, 0.040 mmol, xantphos) were added, degassed and purged with nitrogen three times. The mixture was then heated to 100° C. and stirred under nitrogen for 15 hours. It was then cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with brine (2×5 mL), concentrated, purified with chromatography (v. ethyl acetate/hexane=1/1, Rf=0.1) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.04-2.19 (m, 2 H), 2.57 (t, J=7.9 Hz, 2 H), 3.95 (t, J=6.9 Hz, 2 H), 7.60-7.75 (m, 2 H), 7.84-8.10 (m, 2 H), 8.46 (dt, J=7.9, 2.0 Hz, 1 H), 8.64 (t, J=2.0 Hz, 1 H), 8.82 (dd, J=5.0, 1.8 Hz, 1 H), 9.26 (dd, J=2.4, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].FC(F)(F)C(O)=O.[O:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH:58]=O)[CH2:53][CH2:52]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][CH:21]=2)[N:18]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:58][CH2:57][N:54]4[CH2:55][CH2:56][O:51][CH2:52][CH2:53]4)[CH2:23]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: O=CCN1CCOCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCNC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 27, 0.050 g, 0.08 mmol) was taken up in THF (2 mL) and 2-morpholinoacetaldehyde 2,2,2-trifluoroacetate (0.024 g, 0.10 mmol) and DIEA (0.043 mL, 0.24 mmol) were added. The mixture was stirred at RT for 15 min. then sodium triacetoxyborohydride (0.078 g, 0.37 mmol) was added and reaction was stirred at RT for 6 hrs. The reaction was then quenched with NaHCO3 and extracted with DCM three times. Organics were combined and dried over Na2SO4 then the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using (dichloromethane-methanol) to give (R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-(2-morpholinoethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (0.026 mg, 44%).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].CN(C)[CH:29]=[O:30]>O1CCCC1>[Si:20]([O:19][CH2:18][CH2:17][CH2:16][N:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:7]([CH:29]=[O:30])[C:8]=2[CH:9]=[CH:10]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(Br)cccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(C=O)cccc21

Procedure:
Add tert-butyl lithium (27.07 ml, 46.03 mmol, 1.7 M in pentane) to a solution of 4-Bromo-1-[3-(tert-butyldimethyl-silyloxy)prop-1-yl]-1H-indole (6.76 g, 18.41 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C. Stir the reaction at −78° C. for 30 min, quench with N,N-dimethylformamide (4.7 ml, 64.45 mmol), warm to O° C., quench with pH=7 buffer, and extract into ethyl acetate. Combine the organic layers, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate: hexane gradient (100% hexane to 50% ethyl acetate: hexane over 45 minutes) gives the title compound as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[NH:8][CH2:7][C:6]=2[CH:12]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:10])(=[O:11])[N:8]([CH3:13])[CH2:7][C:6]=2[CH:12]=1
Reactant: O=S1(=O)NCc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CN1Cc2cc(Br)ccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 725.7 %

Procedure:
To a suspension of 5-bromo-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (200 mg, 0.92 mmol) and potassium carbonate (128 mg, 0.92 mmol) in EtOH (2 mL) was added iodomethane (0.2 mL, 3.2 mmol) and the reaction was stirred at room temperature for 18 hours followed by heating to 50° C. for 2 hours. The reaction was cooled, concentrated in vacuo and diluted with DCM (20 mL). The solution was washed with water (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the title compound as a white solid (1.75 g, 83%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[N+:25]([O-:27])[CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:29]([C:31]1[CH:45]=[CH:44][C:34]([O:35][C:36]([CH3:43])([CH3:42])[C:37](OCC)=[O:38])=[CH:33][CH:32]=1)#[N:30]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:28][C:37](=[O:38])[C:36]([O:35][C:34]2[CH:44]=[CH:45][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)([CH3:43])[CH3:42])=[N+:25]([O-:27])[CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C#N)cc1)C(=O)Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Temperature: -78 °C
Yield: 23 %

Procedure:
5 ml of a 1.2M solution of butyllithium in n-hexane were added to a solution of 0.6 g of diisopropylamine in 10 ml of tetrahydrofuran while stirring at -78° C. under a nitrogen atmosphere. The solution was stirred for a further 15 minutes and then 1.07 g of 5-benzyloxy-2-methylpyridine N-oxide in 10 ml of tetrahydrofuran were added. The mixture was allowed to warm to 20° C. stirred for 30 minutes and then cooled to -78° C. 1.16 g of ethyl (4-cyanophenoxy)-2-methylpropionate were added and the mixture was then allowed to warm to 20° C. and was stirred for 16 hours. The mixture was diluted with 50 ml of ethyl acetate and washed in succession with water and sodium chloride solution The organic phase was evaporated and the residue was chromatographed on silica gel using dichloromethane/methanol (94:4) for the elution to give 0.46 g of 5-benzyloxy-2-[3-(4-cyanophenoxy)-3-methyl-2oxobutyl]pyridine N-oxide in the form of a pale yellow
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1>>[CH3:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[CH:3][CH:4]=2)[O:9][C:10]=1[CH3:22]
Reactant: ClCc1cscn1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Agent: Cl
Product: Cc1oc(-c2ccc(OCc3cscn3)cc2)nc1CC(=O)N1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially similar to Intermediate 16 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Intermediate 62) and 4-(chloromethyl)thiazole hydrochloride except KI (1.5 eq.) is also added. MS (ES+) 398.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.[C:24](N1C=CN=C1)([N:26]1[CH:30]=CN=[CH:27]1)=[O:25].CNC>C1COCC1.C(O)C>[CH3:27][N:26]([CH3:30])[C:24]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[C:6]([Cl:21])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12]1)=[O:25]
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: N#N
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)N(C)C)N=C2Cc1c(Cl)cncc1Cl
Yield: 36.1 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, in dry THF (35 ml), under stirring and dry N2 at room temperature, was added with 1,1′-carbonyldiimidazole (0.6 g, 3.72 mmoles), then the mixture was refluxed for 3 hours, cooled, added with 5.6M dimethylamine in ethanol (5 ml) and refluxed again. After 44 hours the mixture was cooled, poured into water/ice and extracted more times with CH2Cl2. The organic phases were washed with 5% NaOH, then with water, anhydrified and concentrated. The residue was flash chromatographed (eluent: hexane/ethyl acetate 1:1), then crystallised from acetonitrile (30 ml) to give 0.44 g of the title compound (yield: 36.4%). m.p.: 160-162GC.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[C:16]2=[CH:15][N:14]=1.Cl.C(Cl)(=O)C.C(N(CC)C(C)C)(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>CO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH2:28][N:27]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:26][CH2:25]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCN(C(=O)OC(C)(C)C)C5)n[nH]c3n2)c1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCN(S(C)(=O)=O)C5)n[nH]c3n2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 6-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (10.0 mg, 0.0191 mmol) in methanol (0.10 mL) was treated at r.t. with HCl solution previously prepared from acetyl chloride (0.1 mL) and methanol (0.1 mL) at 0° C. The mixture was stirred at r.t. for 1 h. The volatiles were evaporated. The residue was dissolved in acetonitrile (0.5 mL) and N,N-diisopropylethylamine (30.0 μL, 0.172 mmol). To the mixture was added methanesulfonyl chloride (2.0 μL, 0.026 mmol). The mixture was stirred at r.t. for 1 h. The volatiles were removed. The residue was dissolved in methanol (0.5 mL) and treated with sodium methoxide (25%, 0.060 mL). After 1 h, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=502.1. 1H NMR (300 MHz, DMSO-d6) δ: 9.39 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.07 (t, J=8.1 Hz, 1H), 4.40 (s, 2H), 3.92 (s, 6H), 3.48 (t, J=5.7 Hz, 2H), 3.04 (d, J=5.7 Hz, 3H), 2.97 (s, 3H).
Reaction SMILES: C[N:2]([CH3:22])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:19][CH:20]=[CH2:21])[C:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=1)=O.NC1[C:28]([C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:30])=[CH:27][NH:26][N:25]=1>C(O)(=O)C>[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[C:29]([C:28]1[CH:27]=[N:26][N:25]2[C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH2:19][CH:20]=[CH2:21])[C:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:22]=12)=[O:30]
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Reactant: C=CCN(C(=O)OCC)c1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: C=CCN(C(=O)OCC)c1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1

Procedure:
A mixture of 0.01 mole of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propenylcarbamic acid, ethyl ester and 0.01 mole of 3-amino-4-furoylpyrazole in 50 ml of glacial acetic acid is refluxed for 12 hours and the solvent removed in vacuo. The residue is partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is separated, dried over anhydrous sodium sulfate and passed through a 2-3 cm thick layer of hydrous magnesium silicate. The filter cake is washed with 2-3 volumes of additional dichloromethane and the filtrate concentrated. Addition of hexane and concentration gives the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Se](=O)=[O:14]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]=[O:14])[CH:3]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: O=[Se]=O
Solvent: O
Product: O=Cc1cc(Cl)c2ccccc2n1
Temperature: 90 °C

Procedure:
4-Chloro-2-methylquinoline (0.4 ml, 0.5M solution in dioxane) was treated with selenium dioxide (0.2 ml, 0.9M solution in 9/1 dioxane/water) and heated to 90° C. overnight. The mixture was cooled to room temperature and diluted with water (1 ml). The mixture was then extracted with ethyl acetate (3×2 ml). The organic extract was then dried in vacuo to give 4-chloro-2-quinolinecarboxaldehyde which was carried forward without further purification. Daptomycin (1 ml, 0.1 M in dry dimethylformamide) was treated successively with 4-chloro-2-quinolinecarboxaldehyde prepared above and diluted in dry dimethylformamide (0.2 ml) and sodium triacetoxyborohydride (0.4 ml, 1.5M in dry dimethylformamide). The mixture was capped and shaken briefly. After 24 h the mixture was treated with water (0.2 ml) and loaded on an IBSIL-C8 5μ 250×20.2 mm column. The column was eluted at 25 ml/min under the gradient conditions of 30-60% acetonitrile in 5 mM ammonium phosphate buffer over 25 min followed by holding at 60% acetonitrile in 5 mM ammonium phosphate buffer for another 10 min. The desired fractions were collected and the acetonitrile was removed by evaporation. The residue was applied to a Bondesil 40μ C8 resin column, washed with water and the product eluted off with methanol. Evaporation of the methanol gave compound 285 as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:22])[N:3]=1.[NH2:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:35]([O:34][C:32](=[O:33])[C@H:24]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:23][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:10]2[C:5]3[C:4](=[O:22])[N:3]=[C:2]([NH2:1])[NH:7][C:6]=3[NH:8][CH:9]=2)=[CH:14][CH:15]=1)[CH3:36]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)O)cc3)c[nH]c2[nH]1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3[nH]c(N)nc(=O)c23)cc1)C(=O)OCC

Procedure:
condensing 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid with diethyl L-glutamate hydrochlorate to give N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl-L-glutamic acid diethyl ester, and then forming a p-toluenesulfonate salt thereof; and
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[Cl-].[Na+]>O1CCCC1.CCOCC>[Si:8]([O:6][CH2:5][CH2:4][CH2:3][OH:7])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
To a suspension of sodium hydride (6.29 g, 262 mmol) in dry tetrahydrofuran (400 ml) was added 1,3-propanediol (20.0 g, 262 mmol) over 5 min and the mixture was stirred at room temperature under dry nitrogen for 1.5 hr. t-Butyldimethylsilyl chloride (39.5 g, 262 mmol) was added portionwise and the mixture was stirred at room temperature for 1.5 hr. Saturated sodium chloride solution (300 ml) then ether (500 ml) were added. The organic portion was dried (magnesium sulphate), filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with ether-hexane (1:2, 3:2) to afford 3-(t-butyldimethylsilyloxy)propan-1-ol as a colourless liquid (41.2 g, 83%); δH (CDCl3) 0.10 (6H, s, CH3), 0.93 (9H, s, C(CH3)3), 1.80 (2H, qu, J 6 Hz, CH2), 2.37 (1H, br.s, OH), 3.87 ( 4H, m, CH2O ).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH3:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C.C(#N)C>[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:2][CH3:1])[CH2:7][CH2:6]1)[CH3:4]
Reactant: CN
Reactant: CCN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: CCN1CCC(NC)CC1
Reaction time: 1 h

Procedure:
To a solution of 40% methylamine in methanol (1.26 g) were added acetonitrile (150 ml), 1-ethyl-4-piperidone (2.0 ml) and acetic acid (0.932 ml), followed by addition of sodium triacetoxyborohydride (6.59 g) and stirring for 1 hr. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (20 ml), and the reaction mixture was concentrated under reduced pressure. The resultant residue was suspended in methanol (20 ml), the solid was removed by filtration and washed with methanol (20 ml). The filtrate was concentrated under reduced pressure, the resultant residue was suspended in tetrahydrofuran (50 ml). The solid was removed by filtration and washed with tetrahydrofuran (100 ml). The filtrate was concentrated under reduced pressure to provide a crude product of the titled compound as a pale yellow oil (3.33 g).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:31]=3[N:32]=2)[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:47].C(OCC)(=O)C.C(OC(C)C)(C)C>O1CCOCC1>[ClH:47].[F:46][C:42]1[CH:41]=[C:40]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28]3[O:29][C:30]4[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:31]=4[N:32]=3)[CH2:24]2)[CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc3cc(C(=O)O)ccc3o2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(c2nc3cc(C(=O)O)ccc3o2)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 35 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylic acid in 1.0 mL of 1,4-dioxane solution was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 1 hour. Diisopropyl ether was added thereto, and the resulting precipitate was collected by filtration, and dried under reduced pressure to obtain 14 mg of 2-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylic acid hydrochloride.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[I:9]I.CCCCCC>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Br:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: II
Reactant: Nc1ccc(Br)nc1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCCCCC
Product: Nc1ccc(Br)nc1I
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a stirred solution of 6-bromo-pyridin-3-ylamine (10.2 g, 0.0580 mol) and Ag2SO4 (18.1 g, 0.0580 mol) in EtOH (150 mL) was added I2 (7.59 g, 0.0580 mol) and the reaction was allowed to stir overnight. At this time hexane (200 mL) was added and the resultant mixture was filtered through Celite. The solvent was removed in vacuo, dissolved in CHCl3 (200 mL), washed with aqueous saturated Na2S2O3 (100 mL), water (1×100 mL), and dried (Na2SO4). The solvent was concentrated in vacuo and the residue was dissolved in hot EtOAc (100 mL), filtered and treated with hexanes (100 mL). Filtration gave 11.2 g (65%) of the title compound as a white crystalline material. 1H-NMR (CDCl3; 400 MHz): δ 7.10 (d, 1H, J=8.2 Hz), 6.74 (d, 1H, J=8.2 Hz), 4.06 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21].Cl>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: O=C(NCCCN1CCOCC1)c1c(Cl)ncnc1Cl
Reactant: N
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncnc(Cl)c1C(=O)NCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
4,6-Dichloro-N-(3-morpholinopropyl)pyrimidine-5-carboxamide (1.13 g, 3.08 mmol) was dissolved in dioxane (10 ml) and cooled in an ice bath. Ammonia solution (2.2 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 15 min and 4 h at room temperature. After dilution with ethyl acetate, this organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield an oil which was rejected. The aqueous phase was neutralized with 2N HCl, extracted with DCM, dried over magnesium sulphate, filtered and the solvent evaporated. An oil was obtained (450 mg, 70% purity, 34% yield) which was used in the next synthetic step without further purification.