Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:7]1([CH3:15])[CH2:8][CH2:9][C:10](=[O:13])[C:11]2[CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=[CH:5][C:6]1=2
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound E) flushed for 15 minutes with a stream of argon, and 6 g (21.7 mmol) of ethyl 4-iodobenzoate in 100 ml of triethylamine was added 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide. The mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid. PMR (CDCl3): δ 1.41 (3H, t, J=7.2 Hz), 1.41 (6H, s), 2.04 (2H, t, J=6.5 Hz), 2.76 (2H, t, J=6.5 Hz), 4.40 (2H, q, J=7.2 Hz), 7.44 (1H, d, J=8.2 Hz), 7.59 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=1.8, 8.2 Hz), 8.04 (2H, d, J=8.4 Hz), 8.15 (1H, d, J=1.8 Hz).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=[O:16])[CH:13]([CH3:15])[CH3:14]>>[CH3:14][CH:13]([CH3:15])[CH:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1)[OH:16]
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CC(C)C=O
Product: CC(C)C(O)c1ccnn1-c1ccccc1
Yield: 57 %

Procedure:
This compound was prepared from 1-phenyl-1H-pyrazole and isobutyraldehyde using the method described in example 10B and isolated as a clear oil in 57% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[C:16]([F:28])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[NH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][O:72][C:73]1[CH:82]=[CH:81][CH:80]=[C:79]([OH:83])[C:74]=1[C:75]([O:77][CH3:78])=[O:76]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:25])(=[O:26])[NH:23][C:22](=[O:27])[CH2:21]2)=[C:16]([F:28])[CH:15]=1)[C:10]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][O:72][C:73]1[CH:82]=[CH:81][CH:80]=[C:79]([OH:83])[C:74]=1[C:75]([O:77][CH3:78])=[O:76])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1c(O)cccc1OCCCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]propanoic acid (16.7 mg, 0.0400 mmol) in DMF (2.00 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19.5 mg, 0.044 mmol). After five minutes N,N-diisopropylethylamine (20.9 μL, 0.120 mmol) and methyl 2-[(5-aminopentyl)oxy]-6-hydroxybenzoate hydrochloride (14.5 mg, 0.050 mmol) were added and the solution stirred at rt for 1 h. The product was directly purified by preparative LCMS to afford product as a white solid (17.8 mg, 68%). 1H NMR (400 MHz, CD3OD): δ 7.45–7.42 (m, 1H), 7.24–7.21 (m, 1H), 7.16–7.10 (m, 2H), 6.50–6.45 (m, 2H), 5.37–5.34 (m, 1H), 4.27–4.24 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (s, 3H), 3.42–3.05 (m, 7H), 2.99–2.94 (m, 1H), 1.79–1.75 (m, 2H), 1.47–1.40 (m, 4H), 1.36 (s, 9H). LCMS found for C30H39FN3O10S (M+H)+: m/z=652.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC=O
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CCCCNCCc1ccc(Cl)c(Cl)c1
Yield: 23.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 2-(3,4-dichlorophenyl)ethanamine (1.27 g, 6.68 mmol) and butyraldehyde (600 μL, 6.68 mmol) were converted to the title compound (390 mg, 24%). 1H NMR (CDCl3) δ 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.06 (dd, J=2.1, 8.3 Hz, 1H), 2.97-2.90 (m, 2H), 2.88-2.81 (m, 2H), 2.75-2.66 (m, 2H), 1.53 (quin, J=7.5 Hz, 2H), 1.34 (qd, J=7.4, 15.0 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 246.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:53][NH2:54]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:54][CH3:53])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 72 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.25, 0.43 mmol), MCPBA (0.081 g, 0.47 mmol) and 2 M methylamine in THF (1 mL) were combined to provide 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as white solid (0.17 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J=2.0 Hz, 1H), 8.81 (s, 1H), 8.60 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.83-7.78 (m, 1H), 7.65 (s, 1H), 7.54-7.47 (m, 4H), 7.43-7.38 (m, 1H), 7.11 (d, J=12.0 Hz, 1H), 6.34 (s, 1H), 3.59 (s, 3H), 2.90 (d, J=4.4 Hz, 1H), 2.05 (s, 3H), 1.23 (s, 9H); MS (ESI) m/z; 555.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]2[CH:18]=[CH:17][S:16][C:13]=2[NH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[K+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]2[CH:18]=[CH:17][S:16][C:13]=2[N:14]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2sccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cn(S(=O)(=O)c2ccccc2)c2sccc12
Reaction time: 8 h

Procedure:
A mixture of N-(t-butoxycarbonyl)-2-(6H-thieno[2,3-b]pyrrol-4-yl)ethylamine (54 mg, 0.2 mmol), phenylsulfonyl chloride (70 mg, 0.22 mmol) and KOt-Bu (0.22 mL 1 M solution in THF, 0.22 mmol) in THF is shaken at ambient temperatures for 8 h and concentrated in vacuo. The resultant residue is dissolved in THF, treated with 4N HCl in dioxane (2 mL) shaken at room temperature for 16 h and concentrated in vacuo. This residue is dissolved in a mixture of DMSO, methanol and water and purified by preparative HPLC1, to afford the title product, [M+H]307, retention time (RT) 1.53 min. 1 Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH2:20])=[O:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:20][C:4]1[C:5]([Cl:8])=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=1)=[O:13]
Reactant: CNC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H]1CCCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
2,5,6-trichloropyrimidine (368 mg, 2.0 mmol), cis-2-amino-cyclohexanecarboxylic acid methylamide (308 mg, 2.0 mmol), and N,N-diisopropylethylamine (387 mg, 3.0 mmol) were combined in 10 mL isopropyl alcohol and stirred at room temperature for 24 hours. The reaction was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated and was dried (sodium sulfate) to afford a solid which was purified on silica gel (1% to 3% methanol:dichloromethane gradient elution) to afford 502 mg (83%) of cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methylamide as a white foam. Mp: 108° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]([CH3:9])[C:3]1=[O:10].[CH3:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15].C1C=CC=CC=1>O>[CH3:12][C:13]1([CH3:18])[CH2:14][O:15][C:6]2([CH2:5][C@@H:4]([CH3:9])[C:3](=[O:10])[C:2]([CH3:1])([CH3:11])[CH2:7]2)[O:8][CH2:16]1
Reactant: CC(C)(CO)CO
Reactant: C[C@@H]1CC(=O)CC(C)(C)C1=O
Solvent: O
Solvent: c1ccccc1
Product: C[C@@H]1CC2(CC(C)(C)C1=O)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of (-)-(6R)-2,2,6-trimethyl-1,4-cyclohexandione (924 mg, 6.0 mmol), 2,2-dimethyl-1,3-propandiol (791 mg, 7.6 mmol), pyridinium p-tosylate (34 mg, 0.13 mmol), and benzene (15 mL) was heated to reflux under a Dean-Stark water separator for 4 h. The reaction mixture was allowed to cool to room temperature before it was washed with H2O, and dried over anhydrous Na2SO4. Evaporation of solvent gave a pale yellow oil (1.43 g) as the crude product, which was distilled using the Kugel-rohr apparatus (80°-100° C., 0.03 mm Hg) to give pure ketal as a colorless oil (1.31 g, 91%), [a]D -87.7° C. (c 1.10, CH3OH); ir: 1710 cm-1; 1H nmr d: 0.85 (s, 3H, CH3), 0.91 (d, J=6.6 Hz, 3H, CHCH3), 0.97 (s, 6H, 2 CH3), 1.16 (s, 3H, CH3), 1.56 (dd, J=13.5, 13.5 Hz, H-11ax), 1.58 (d, J=14.2 Hz, H-7ax), 2.38 (ddd, J=13.5, 5.3, 3.8 Hz, 1H, H-11eq), 2.47 (dd, J=14.2, 3.8 Hz, 1H, H-7eq), 2.85 (m, 1H, CHCH3), 3.41 and 3.48 (2dd, J=11.4, 1.6 Hz, 2H, 2 equatorial H at C2 and C4), 3.53 and 3.61 (2d, J=11.4 Hz, 2H, 2 axial H at C2 and C4); ms m/e: 240 (M+, 0.58), 141 (27), 155 (98), 83 (27), 69 (100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:29][CH2:28][N:27]([CH2:26][C:25]2[CH:34]=[CH:35][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:31][CH2:32]1)=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(Cl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 13.5 mmol) and (4-chloro-benzyl)-bis-(2-chloro-ethyl)-amine (4.9 g, 16.2 mmol). Yield 3.5 g (53%); white crystals; MP 91.8° C.; MS: 490 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:35][C:34](=O)[NH:33][N:32]=2)=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[C:34]1[CH:35]=[C:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[NH:32][N:33]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Product: COc1ccc(-c2cc(-c3ncnc4cc(OCC5CCN(C)CC5)c(OC)cc34)n[nH]2)cc1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described in Example 15, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (140 mg, 0.435 mol), (prepared as described for the starting material in Example 15), was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (100 mg, 0.52 mol), (prepared as described for the starting material in Example 10), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(5-(4-methoxyphenyl)pyrazol-3-yl)quinazoline (174 mg, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=2[Br:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:20][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])[CH:10]=2)[C:15]=1[Br:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(Br)c(O)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2cc(CNC(=O)OC(C)(C)C)ccc2c1Br
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamic acid tert-butyl ester (0.89 g, 2.5 mmol), prepared in the previous step, potassium carbonate (1.7 g, 12.5 mmol), and methyl bromoacetate (1.26 mL, 2.75 mmol) in 10 mL of DMF was stirred under nitrogen for 18 h (overnight). The reaction was diluted with ethyl acetate and extracted three times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give [1-bromo-6-(tert-butoxycarbonylamino-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (1.016 g, 96%) as an off white solid, mp 96-100° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12](Cl)[CH:11]=[C:10](Cl)[C:9]=2[Cl:16])=[CH:6][N:5]=[C:4]([N:17]([CH3:19])[CH3:18])[N:3]=1.[Cl:20]C1C=C(Cl)C=CC=1CC#N>>[CH3:19][N:17]([CH3:18])[C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=2[Cl:16])=[CH:6][N:5]=1
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CN(C)c1ncc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Product: CN(C)c1ncc(-c2ccc(Cl)cc2Cl)c(N)n1

Procedure:
This compound was prepared in an analogous manner to the compound of Example 10 from 2,4-dichlorophenylacetonitrile (Aldrich), mp. 151° C.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[C:37]([F:39])[C:36]([O:40][CH3:41])=[CH:35][C:34]=1[F:42])[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:42][C:34]1[CH:35]=[C:36]([O:40][CH3:41])[C:37]([F:39])=[CH:38][C:33]=1[C@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH2:18][NH:19][CH3:32]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: COc1cc(F)c([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1F
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(OC)cc1F

Procedure:
Compound 32 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [389 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 10.03-9.86 (m, 1H), 9.04 (s, 1H), 8.98 (d, J=4.5 Hz, 1H), 8.56 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.24-8.07 (m, 1H), 7.42 (dd, J=12.1, 7.0 Hz, 1H), 7.09 (dd, J=11.5, 7.2 Hz, 1H), 5.72 (s, 1H), 3.82 (s, 3H), 3.11 (dd, J=12.3, 8.5 Hz, 1H), 2.85 (dd, J=12.4, 5.3 Hz, 1H), 2.54 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[O:8].[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:21][C:19](=[CH2:20])[C:18]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[O:8])=[O:22]
Reactant: C=C(C)C(=O)O
Reactant: CCCC1CCC(C(=O)OCCCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C(C)C(=O)OCCCCOC(=O)C1CCC(CCC)CC1

Procedure:
4-Propyl-cyclohexanecarboxylic acid 4-bromo-butyl ester (9.4 g, 30.8 mmol), methacrylic acid (8.0 g, 92.4 mmol) and potassium carbonate (17.0 g, 123.2 mmol) are stirred at 50° C. in dimethyl sulphoxide (200 ml) over night. A solid precipitate is removed by filtration and washed with diethyl ether. The filtrate is washed with water, removed, dried and evaporated to dryness. Purification is achieved by flash column chromatography using toluene as eluant to give 21 as an oil.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]([OH:5])[CH3:4].CCN(CC)CC.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:5][CH:3]([CH:2]([O:6][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:1])[CH3:4])(=[O:17])=[O:16]
Reactant: CC(O)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of butane 2,3-diol (15 g, 0.166 mol) and Et3N (57.7 mL, 0.415 mol) in CH2Cl2 (150 mL) at 0° C. was slowly added a solution of CH3SO2Cl (32.1 mL, 0.415 mol) in CH2Cl2 (75 mL). The mixture was stirred at 0° C. for 2 h and diluted with CH2Cl2. The mixture was washed with water, 1N HCl, 5% aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford butane-2,3-diyl dimethanesulfonate (40 g, 98%) as a light yellow oil. 1HNMR (CDCl3): δ4.9 (m, 2H, CH), 3.05 (s, 6H, H3), 1.4 (m, 6H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].[CH2:13]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:23]1([C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:22])[C:24](=[O:28])[CH2:25][CH2:26][CH2:27]1)[CH3:2]
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCCC1(C(=O)OCc2ccccc2)CCCC1=O

Procedure:
To a 100 ml. RB flask was added 13 g. to Ethyl-7-bromoheptanoate and 12.8 g. of 2-benzyloxycarbonylcyclopentanone. The reactants were dissolved in 50 ml. of anhydrous acetone and refluxed over 17 g. of anhydrous potassium carbonate under nitrogen for 20 hours. The reaction mixture was then cooled and filtered and the filtrate evaporated to afford 22.1 g. of crude oil, which was not further purified at this stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[C:27]([F:30])([F:29])[F:28])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (500 mg, 1.31 mmol) and trimethyl(trifluoromethyl)silane (582 μL, 3.94 mmol) in tetrahydrofuran (6.5 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 131 μL, 0.131 mmol) at 0° C. After 15 min, hydrochloric acid (1.0 M, 2.0 mL) was added. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (590 mg, 1.30 mmol, 99%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C(=O)([O-])[O-].[NH4+:18].[NH4+]>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:18][C:11]2=[O:13]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: O=C1NC(=O)c2cc(O)ccc21
Temperature: 120 °C
Yield: 72.7 %

Procedure:
A mixture of 4-hydroxyphthalic acid (5.0 g, 27.0 mmol), acetic acid (25 mL), and ammonium carbonate (5.3 g, 55 mmol) was heated at 120° C. for 45 min followed by heating at 160° C. for 2 h. After cooling to room temperature, the reaction mixture was half-evaporated and then the reaction mixture was basified to pH 10 with 1 N NaOH followed by acidification to pH 5 at 0° C. with concentrated HCl. The resulting precipitate was filtered off, washed with water, dried at 60° C. under high vacuum over night, to afford the title compound (3.2 g, 71%) as an off-white crystalline solid. MS: m/e=162.1 (M−H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BX) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; MS (ESI): 483.2 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:39])[CH:32]([O:36][CH2:37][CH3:38])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:39])[CH:32]([O:36][CH2:37][CH3:38])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: CCOC(=O)C(OCC)C(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CCOC(=O)C(OCC)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-ethoxy-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (94%). MS: m/e=517(M+H+).