Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH:25]([CH3:34])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=[O:30])[CH:25]([CH3:34])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CCC1C(=O)O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-methylpiperidine-4-carboxylate (750 mg, 1.62 mmol, 1.0 eq) in THF/H2O (8/1, 9.0 mL) was added NaOH (130 mg, 3.24 mmol, 2.0 eq). The mixture was heated to 60° C. and stirred for 16 h. After cooling down to room temperature, the reaction mixture was adjusted to pH=7 with aq. HCl. The solvent was removed in vacuo to give the residue, which was purified by silica gel (DCM/MeOH=15:1) to give 1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-methylpiperidine-4-carboxylic acid as a white solid (620 mg, Y: 88%). ESI-MS (M+H)+: 438.3. HPLC: 100.00%; 1H NMR (400 MHz, CDCl3) δ ppm 10.82 (br, 1H), 7.65-7.54 (m, 3H), 7.41-7.40 (m, 1H), 7.04-7.02 (m, 2H), 4.20-4.14 (m, 1H), 3.85 (s, 2H), 3.15-3.07 (m, 2H), 2.77-2.71 (m, 1H), 2.50-2.46 (m, 1H), 2.18-2.16 (m, 3H), 1.96-1.92 (m, 2H), 1.81-1.78 (m, 2H), 1.36-0.96 (m, 9H), 0.82 (s, 9H).
Reaction SMILES: C([C:3]1(CC)[CH:8]([C:9]([CH:11]([C:15]([O-:17])=[O:16])C([O-])=O)=[O:10])[C:7]([F:18])=[C:6]([O:19][CH:20]([F:22])[F:21])[C:5]([F:23])=[C:4]1[F:24])C.O.[C:28]1(C)C=CC(S(O)(=O)=O)=C[CH:29]=1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:22][CH:20]([F:21])[O:19][C:6]1[C:7]([F:18])=[C:8]([CH:3]=[C:4]([F:24])[C:5]=1[F:23])[C:9]([CH2:11][C:15]([O:17][CH2:28][CH3:29])=[O:16])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC1(CC)C(F)=C(F)C(OC(F)F)=C(F)C1C(=O)C(C(=O)[O-])C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
The whole of the diethyl-3-difluoromethoxy-2,4,5trifluorobenzoylmalonate [(XIV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (a) above] was dissolved in 200 ml of dioxane, and then 4.52 g (0.0238 moles) of p-toluenesulfonic acid monohydrate were added to the resulting solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. 100 ml of water and 2.52 g (0.03 moles) of sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 5.66 g of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate as a reddish brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:35])[CH:10]=1.N1C=CC=CC=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)ccc32)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)ccc32)c1
Yield: 42 %

Procedure:
To a solution of 2′,4′-difluoro-5-(5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine (60 mg, 0.126 mmol) in DCM was added pyridine (19 mg, 2.52 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (19 mg, 0.152 mmol, 1.2 eq). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg). 1H NMR (300 MHz, CD3OD): δ 8.92 (s, 1H), 8.3 (d, 1H), 8.06 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77-7.69 (m, 5H), 7.45 (m, 1H), 6.56 (m, 1H), 3.92 (s, 3H), 3.28-3.27 (m, 4H), 1.6-1.49 (m, 6H); LC-MS (ESI): Calculated mass: 564.6; Observed mass: 565.4 [M+H]+ (rt: 1.46 min).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([N:28]=[CH:29][N:30]=4)[C:20]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(C)C.Br[CH2:32][C:33]([NH2:35])=[O:34]>>[NH:26]1[CH:27]=[C:23]([C:20]2[N:19]3[N:28]=[CH:29][N:30]=[C:18]3[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([CH:7]4[CH2:8][CH2:9][N:4]([CH2:32][C:33]([NH2:35])=[O:34])[CH2:5][CH2:6]4)=[CH:15][CH:14]=3)=[N:22][CH:21]=2)[CH:24]=[N:25]1
Reactant: NC(=O)CBr
Reactant: CC(C)N1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ncnc34)cc2)CC1
Product: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ncnc34)cc2)CC1

Procedure:
This compound may be prepared using methods as described for Compound 84, using 2-bromoacetamide in step 1. LCMS: Rt=0.81 min (100%), m/z (ESI) 418 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:51]([NH:48][C:49]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)=[O:50])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2-isocyanato-2-methyl-propane as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.32 (m, 2H), 8.13 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.22 (d, 1H), 7.09 (m, 1H), 7.01 (d, 1H), 6.89 (d, 1H), 6.75 (d, 1H), 5.71 (s, 1H), 3.91 (d, 2H), 2.90 (m, 2H), 2.82 (m, 2H), 2.61 (m, 2H), 2.25 (d, 2H), 1.90 (m, 1H), 1.62 (m, 2H), 1.23 (s, 9H), 1.10 (m, 2H). LCMS for C30H37ClN7O2 (M+H)+: m/z=562.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][NH:19][C:20]1[C:21]3[C:26]([N:27]=[C:28]4[C:33]=1[CH:32]=[C:31]([O:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:30]=[CH:29]4)=[CH:25][C:24]([Cl:43])=[CH:23][CH:22]=3)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])=[CH:10]1)=[N:5]2.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>ClCCl>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:43][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20]([NH:19][CH2:18][CH2:17][NH:16][C:12]1[C:13]3[C:4]([N:5]=[C:6]4[C:11]=1[CH:10]=[C:9]([O:44][CH2:45][C:46]([OH:48])=[O:47])[CH:8]=[CH:7]4)=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)=[C:33]1[C:28]([CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:32]1)=[N:27]2
Reactant: CC(C)(C)OC(=O)COc1ccc2nc3cc(Cl)ccc3c(NCCNc3c4ccc(Cl)cc4nc4ccc(OCC(=O)OC(C)(C)C)cc34)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc2nc3cc(Cl)ccc3c(NCCNc3c4ccc(Cl)cc4nc4ccc(OCC(=O)O)cc34)c2c1

Procedure:
A solution of N,N′-bis[6-chloro-2-(tert-butoxycarbonyl)methoxy-9-acridinyl]-1,2-ethanediamine (12 mg, 0.12 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (12 mL) was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC (YMC ODS-AQ, 100×250 mm, 80 mL/min, 26% acetonitrile/water/0.1% trifluoroacetic acid, UV detection at 254 nm) to give the title compound as a yellow solid. MS(ES) m/e 631.3 (M+H)+.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:43])=[C:30]([C@:32]23[CH2:40][O:39][CH2:38][C@@:37]2([F:41])[CH2:36][S:35][C:34]([NH2:42])=[N:33]3)[CH:31]=1.[O:44]1[CH2:47][CH2:46][CH:45]1[CH2:48][O:49][C:50]1[N:51]=[CH:52][C:53]([C:56](O)=[O:57])=[N:54][CH:55]=1>ClCCl>[NH2:42][C:34]1[S:35][CH2:36][C@:37]2([F:41])[CH2:38][O:39][CH2:40][C@:32]2([C:30]2[CH:31]=[C:26]([NH:25][C:56]([C:53]3[CH:52]=[N:51][C:50]([O:49][CH2:48][CH:45]4[CH2:46][CH2:47][O:44]4)=[CH:55][N:54]=3)=[O:57])[CH:27]=[CH:28][C:29]=2[F:43])[N:33]=1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)COC[C@@]2(F)CS1
Reactant: O=C(O)c1cnc(OCC2CCO2)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(OCC5CCO5)cn4)ccc3F)COC[C@@]2(F)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride 50 wt % solution in ethyl acetate (8.90 μL, 1.50 mmol) is added to a microwave vial containing a mixture of (4aR,7aS)-7a-(5-amino-2-fluoro-phenyl)-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]thiazin-2-amine (81.2 mg, 0.285 mmol), 5-(oxetan-2-ylmethoxy)pyrazine-2-carboxylic acid (140 mg, 0.300 mmol) and anhydrous dichloromethane (10 mL). The vial is sealed and the mixture stirred at room temperature overnight. The mixture is then partitioned between water and dichloromethane and the layers separated through a Phase Separating cartridge. Organics are combined and the solvent evaporated under reduced pressure. The resulting oil is dissolved in methanol, filtered, and purified by preparative-HPLC (Phenomenex Gemini 10 μm 50*150 mm C-18) (CH3CN and water with 10 mM ammonium bicarbonate, 10% to 100% CH3CN over 10 minutes at 120 ml/min) (1 injection). Fractions bearing product are concentrated to dryness overnight in a centrifugal evaporator to give the title compound as a white solid (40 mg, 28%). ES/MS (m/e): 478.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][NH:26]C(OC(C)(C)C)=O)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[C:21]([O:23][CH3:24])=[O:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:26][CH2:25][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[C:21]([O:23][CH3:24])=[O:22])=[O:14]
Reactant: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a round bottom flask was added (R)-methyl 1-((S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoyl)piperidine-2-carboxylate (1.80 gm, 3.88 mmol), DCM (5 mL) and TFA (5 mL). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was then concentrated and dried under vacuum for 3 hr to afford (R)-methyl 1-((S)-3-amino-2-(benzyloxycarbonylamino)propanoyl)piperidine-2-carboxylate trifluoroacetate (1.87 g, 3.92 mmol, 100% yield) as a colorless oil. Anal. Calcd. for C18H25N3O5 m/z 363.4. found: 364.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:1]1[CH2:2][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4]1)(=[O:29])[CH3:28]
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (100 mg, 0.42 mmol) in dichloromethane (10 mL) cooled to 0° C. was added diisopropylethylamine (160 mg, 1.26 mmol) and acetic anhydride (45 mg, 0.51 mmol). The resulting mixture was stirred at RT for 3 h before it was quenched by addition of water (10 ml). The aqueous layer was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with saturated aqueous NaHCO3 (10 ml), dried (Na2SO4), filtered and concentrated. Purification by silica FCC (using a gradient of eluents; 100:0 to 99:1 DCM:2M NH3 in MeOH) followed by purification by preparative HPLC (Method 2) gave the title compound (35 mg, 30% yield) as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].[ClH:25]>O1CCOCC1>[ClH:25].[N+:22]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc([N+](=O)[O-])c(N)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(NC2CCCNC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
610 mg (1.62 mmol) of tert-butyl 3-[(6-amino-5-nitropyridin-2-yl)amino]piperidine-1-carboxylate (Example 41A) were dissolved in 40 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 30 min. After the reaction had gone to completion, the solvent was removed completely. This gave 662 mg of the crude product.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26]([O:28]CC)=O)[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:31])=[C:13]([C:26]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:28])[C:14](=[O:25])[N:15]2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccn2C)c1=O
Product: Cn1ccnc1Cn1c(=O)c(C(=O)NC2CC2)c(O)c2ncc(Cc3ccccc3)cc21

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine using methods similar to those described in Example 11. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.02 (1H, br), 8.57 (1H, s), 8.45 (1H, br s), 7.30-7.21 (5H, m), 7.01 (1H, br s), 6.83 (1H, s), 5.69 (2H, br), 4.17 (2H, s), 3.67 (3H, s), 2.95 (1H, m), 0.91 (2H, m), 0.71 (2H, m); HRMS calcd for C24H23N5O3+H+: 430.1879. Found: 430.1877.
Reaction SMILES: C(OC([N:6]1[CH2:17][CH:9]2[C:10]3[CH:11]=[C:12]([Br:16])[S:13][C:14]=3[CH2:15][CH:8]2[CH2:7]1)=O)C.I[Si](C)(C)C>C(Cl)Cl.CO>[Br:16][C:12]1[S:13][C:14]2[CH2:15][CH:8]3[CH2:7][NH:6][CH2:17][CH:9]3[C:10]=2[CH:11]=1
Reactant: CCOC(=O)N1CC2Cc3sc(Br)cc3C2C1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: Brc1cc2c(s1)CC1CNCC21

Procedure:
The product of step c) (20.9 mg, 0.07 mmol) in CH2Cl2 (330 μl) was treated with iodotrimethylsilane (19.8 mg, 0.099 mmol) at 50° C. for 16 hours. The solvent was evaporated in vacuo leaving a brown residue that was dissolved in MeOH and a portion purified by preparative LC/MS to give the title compound. 1H NMR (300 MHz, CDCl3, ppm) 2.76-2.81 (m, 1H); 2.95-3.03 (m, 1H); 3.12-3.22 (m, 2H); 3.44-3.61 (m, 3H); 3.81-3.85 (m, 1H); 6.78 (s, 1H); 9.20-9.4 (br s, 2H); MS calculated for C9H10BrNS+H 244, observed 244, 246.
Reaction SMILES: [CH2:1]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br-:20].[Li+]>ClCCl>[Br:20][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:12]1[CH:18]=[CH:19][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(O)CBr)cc1
Reaction time: 3 h

Procedure:
1.17 g (4.46 mmol) 2-(4-octyl-phenoxymethyl)oxirane are dissolved in 10 ml absolute dichloromethane and mixed with 1.34 g (22.3 mmol) silica gel and with 1.16 g (13.4 mmol) lithium bromide. The suspension is concentrated almost to dryness on the rotary evaporator and allowed to stand at room temperature for 3 hours. The reaction batch is mixed with dichloromethane, filtrated on cotton wool and concentrated on the rotary evaporator. Taking up the suspension in diethyl ether, washing with water, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator yield the product as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:24][CH2:21][CH2:22][CH3:23])#[N:20]
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Reactant: CCCN
Product: CCCN=C(NC#N)Nc1cc(Cl)cc(Cl)c1
Yield: 23 %

Procedure:
N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and n-propylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (ethyl acetate/heptane 1:3) to give the title compound (60 mg, 23%) as white crystals. Mp 141-143° C.; 1H-NMR (CDCl3): δ 0.92 (d, 6H), 1.58 (sextet, 2H), 3.25 (q, 1H), 5.1 (br, 1H), 7.19 (m, 2H), 7.25 (m, 1H), 7.95 ppm (br, 1H); MA calc for C11H12Cl2N4 : C, 48.73%; H, 4.46%; N, 20.66%. Found: C, 49.02%; H, 4.55%; N 20.27%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:18]([N:20]=[C:21]=NCCCN(C)C)C.CN(CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1.CNC>CN(C)C=O>[CH3:18][N:20]([CH3:21])[C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-[N-(benzyloxycarbonyl)amino]propionic acid (0.70 g, 3.14 mmol) was dissolved in N,N-dimethylformamide (15 ml), and 1-(dimethylaminopropyl)-3-ethylcarbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.13 mmol), 1-hydroxybenzotriazole (0.48 g, 3.13 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 2.40 ml, 4.80 mmol) were added, followed by stirring at room temperature for 3 days.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.Cl.CO.[CH3:18]COC(C)=O>COC(OC)(C)C>[CH3:18][O:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: COC(C)(C)OC
Solvent: CO
Product: COC(=O)c1ccc2cc(O)ccc2c1
Reaction time: 16 h

Procedure:
Treat a mixture of 6-hydroxy-2-naphthoic acid (4.45 g, 23.6 mmol) in 2,2-dimethoxypropane (235 mL) with conc. HCl (24 mL) and then MeOH (60 mL). Stir the reaction at RT for 16 h and then at 55° C. for 16 h. Pour the reaction mixture into EtOAc (250 mL) and wash with brine (3×100 mL). Dry the organic layer over Na2SO4, concentrate the filtrate, and chromatograph the concentrated filtrate (0.5 kg silica gel, 5:95 to 15:85 EtOAc:hex) to give the title compound (4.77 g, quant). MS (ES) m/e 203 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:16]=O.C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:28]O>O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:16]#[N:28]
Reactant: NO
Reactant: CC(C)Nc1ncnc2cc(O)c(C=O)cc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Nc1ncnc2cc(O)c(C#N)cc12
Temperature: 130 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
7-Hydroxy-4-(isopropylamino)quinazoline-6-carbaldehyde (310 mg, 1.34 mmol) is presented as an initial charge in acetic acid (7 mL, 81 mmol) and admixed with sodium acetate (366 mg, 3.3 mmol) and also hydroxylamine hydrochloride (186 mg, 2.68 mmol). The batch is stirred at 130° C. for 18 hours. After cooling to room temperature, the batch is diluted with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate. Removal of the solvent and also chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) of the residue gives the desired product in 38% yield (116 mg).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:8]([NH:12][CH2:5][CH2:6][NH:7][C:3](=[O:4])[CH2:1][CH3:2])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCC1=NCCO1
Reactant: CC(C)(C)N
Agent: CC(=O)[O-]
Agent: [Zn+2]
Product: CCC(=O)NCCNC(C)(C)C
Yield: 64 %

Procedure:
Under the same conditions as Example 13, 2.5 gm (25 mmoles) of 2-ethyl-2-oxazoline, 1.84 gm (25 mmoles) of t-butylamine and 49.4 mg (0.27 mmole) of zinc acetate are reacted to yield 64 percent N-(2-t-butylaminoethyl)propionamide.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([CH2:29][Cl:28])[CH:31]=2)[CH:10]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.1 %

Procedure:
Triethylamine (1.55 ml) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (3.0 g), 3-chloromethylbenzoyl chloride (2.76 g) and methylene chloride (50 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under water. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. There was thus obtained the title compound (4.8 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.96 (s, 6H), 4.84 (s, 2H), 6.9 (d, 1H), 7.26 (m, 3H), 7.5-7.7 (m, 3H), 7.8-8.1 (m, 4H), 9.97 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M−H− 420.