Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:59][NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:52]=[CH:53][C:54]=1[CH2:55][N:56]([CH3:58])[CH3:57])[C:19]([NH:21][C@H:22]([B:39]1[O:47][CH:46]2[C:41]([CH3:51])([CH:42]3[CH2:48][CH:44]([CH2:45]2)[C:43]3([CH3:50])[CH3:49])[O:40]1)[CH2:23][C:24]1[C:25]([O:37][CH3:38])=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@@H:12]([CH2:59][NH:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:52]=[CH:53][C:54]=1[CH2:55][N:56]([CH3:57])[CH3:58])[C:19]([NH:21][C@H:22]([B:39]1[O:47][CH:46]2[C:41]([CH3:51])([CH:42]3[CH2:48][CH:44]([CH2:45]2)[C:43]3([CH3:50])[CH3:49])[O:40]1)[CH2:23][C:24]1[C:25]([O:37][CH3:38])=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[O:20])=[O:14]
Reactant: COc1c(C[C@H](NC(=O)c2ccc(CN(C)C)c(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1c(C[C@H](NC(=O)c2ccc(CN(C)C)c(NC(=O)[C@@H](N)CNC(=O)OC(C)(C)C)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 81 %

Procedure:
To tert-butyl 3-((2R)-2-(3-((S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanamido)-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (130 mg) in MeOH (20 mL was added 10% Pd/C (20 mg). The reaction mixture was stirred under H2 balloon for 6 hr. The catalyst was removed by filtration and MeOH removed under reduced pressure to afford the product (90 mg) which was carried on to the next step.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH2:4].[NH2:21][C:22]1[C:23](OCC)=[N:24][S:25](=[O:33])(=[O:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH:4][C:23]1[C:22]([NH2:21])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:25](=[O:32])(=[O:33])[N:24]=1
Reactant: NCC(O)COCc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=O)C1=C(N)C(OCC)=NS1(=O)=O
Solvent: CC#N
Product: CCOC(=O)C1=C(N)C(NCC(O)COCc2cccc(CN3CCCCC3)c2)=NS1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
1.39 g (5 mmol) of 2-hydroxy-3-[3-(1-piperidylmethyl)benzyloxy]propylamine are added dropwise to a suspension of 1.24 g (5 mmol) of 4-amino-3-ethoxy-5-ethoxycarbonylisothiazole-1,1-dioxide in 10 ml of acetonitrile and the mixture is stirred for 5 hours at room temperature. The residue obtained after evaporation of the solvent under vacuum is chromatographed with methanol against silica gel. The main fraction yields 2.06 g (86%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[C:17](Cl)[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1ncc(CO)n1Cc1ccc(O)cc1
Reaction time: 0.08 h
Yield: 110.9 %

Procedure:
A mixture of 1.00 g of 10% palladium/carbon and 1.00 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol was stirred at 25° for five minutes. Hydrogen gas was bubbled into the solution, and the mixture was stirred under hydrogen gas (1 atm.) at 25° for 2 hours. The mixture was filtered, and the resulting solution concentrated in vacuo to furnish 0.75 g of 1-(4-hydroxybenzyl)-2-butyl-5-hydroxymethylimidazole; NMR (200 Mhz, DMSO-d6): δ 9.75 (bs, 1H); 7.55 (s, 1H); 6.91 (A2B2, 4H); 5.80 (bs, 1H); 5.35 (s, 2H); 4.45 (s, 2H); 2.89 (t, 2H); 1.44 (quint, 2H); 1.21 (sext., 2H); 0.8 (t, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:26][CH3:27])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Yield: 94 %

Procedure:
7-Benzyloxy-6-methoxy-4-phenoxyquinazoline (36.95 g, 105.5 mmol) was suspended in TFA (420 ml) and heated at reflux for 3 hours. The reaction mixture was allowed to cool and evaporated under vacuum. The residue was stirred mechanically in water then basified with saturated aqueous sodium hydrogen carbonate solution and stirred overnight. The water was decanted and the solid suspended in acetone. After stirring the white solid was collected by filtration, washed with acetone and dried to give 7-hydroxy-6-methoxy-4-phenoxyquinazoline (26.61 g, 96%).
Reaction SMILES: [I:1][C:2]1[NH:3][C:4]([I:8])=[C:5]([I:7])[N:6]=1.[H-].[Na+].[C:11]([NH:18][CH2:19][CH2:20]Br)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][N:3]1[C:4]([I:8])=[C:5]([I:7])[N:6]=[C:2]1[I:1])([CH3:17])([CH3:16])[CH3:15]
Reactant: Ic1nc(I)c(I)[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1c(I)nc(I)c1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a yellow solution of 2,4,5-triiodo-1H-imidazole (15.295 g; 34.313 mmol) in anhydrous DMF (200 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (2.058 g; 51.469 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (11.534 g; 51.469 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting mixture was further heated at 100° C. for 1 h. The reaction mixture was cooled to 0° C., and water (200 ml) was added slowly. This mixture was extracted with ether (5×200 ml). The combined organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The crude was purified by FC (heptane/EA=3/2) to give the pure product [2-(2,4,5-triiodo-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a colorless solid which was further dried under HV (8.540 g; 42%). LC-MS: tR=0.93 min.; [M+H]+=589.89 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[CH3:15])=[C:4](F)[CH:3]=1.ClC1C=CC(C2C=CC=CC=2C(N)C)=C(F)C=1.C(N(CC)CC)C.COC1C=CC(C(Cl)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([CH:14]([CH3:15])[N:16]([C:17]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[O:26])[C:4]=2[CH:3]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: COc1ccc(C(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)cc1
Agent: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Agent: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CC1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1ccc(O)cc1

Procedure:
N-[1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzamide—The title compound was prepared from 1-(4′-chloro-2′-fluoro-biphenyl-2-yl)-ethylamine (1 g, 4 mmol), triethylamine (614 uL, 4.4 mmol), and 4-methoxybenzoyl chloride (683 mg, 4 mmol) according to the procedure and in the same manner as described in Example 24, step c. The crude residue was immediately purified on a Biotage® (40 Mi) column for flash column chromatography (5-30% methyl tert-butylether in hexane) resulting in the isolation of 1.22 g (79%) of a white solid. mp 165-165.9° C.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 3 H) 3.80 (s, 3 H) 4.94 (s, 1 H) 6.97 (d, J=8.79 Hz, 2 H) 7.15 (d, J=7.50 Hz, 1 H) 7.30 (s, 1 H) 7.43 (m, 2 H) 7.60 (m, 3 H) 7.82 (d, J=7.50 Hz, 2 H) 8.66 (s, 1 H). MS (ESI) m/z 384/386 ([M+H]+); Anal. calcd for C22H19ClFNO2: C:68.84 H:4.99 N:3.65 Found: C:68.81 H:5.07 N:3.65.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=PC=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12](N)=[S:13]>C(O)C>[CH:6]1[NH:7][C:2]2[C:12]([N:11]=[CH:9][NH:10][C:3]=2[N:5]=1)=[S:13]
Reactant: Clc1ncnc2pc[nH]c12
Reactant: NC(N)=S
Solvent: CCO
Product: S=c1nc[nH]c2nc[nH]c12

Procedure:
The hypoxanthine analog from Example 3 is reacted with POCl3 at reflux temperature for 50 min to form 7-chloro-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 14). Reaction of compound 14 with thiourea in boiling ethanol produced the 6-thiopurine analog 1,3-azaphospholo[4,5-d]pyrimidin-7(1H, 6H)-thione (compound 15). Compounds 14 and 15 are prepared as follows:
Reaction SMILES: C(NC1SC(C(N[C@H](C(OCC)=O)CCC(OCC)=O)=O)=CC=1)C#C.[O:26]=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][N:38]([CH2:56][C:57]#[CH:58])[C:39]3[S:43][C:42]([C:44]([NH:46][C@H:47]([C:53]([O-:55])=[O:54])[CH2:48][CH2:49][C:50]([O-:52])=[O:51])=[O:45])=[CH:41][CH:40]=3)[CH:35]=2)[N:30]=[CH:29][N:28]1COC(=O)C(C)(C)C>>[O:26]=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][N:38]([CH2:56][C:57]#[CH:58])[C:39]3[S:43][C:42]([C:44]([NH:46][C@H:47]([C:53]([OH:55])=[O:54])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:45])=[CH:41][CH:40]=3)[CH:35]=2)[N:30]=[CH:29][NH:28]1
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])s1
Agent: C#CCNc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)s1
Product: C#CCN(Cc1ccc2nc[nH]c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)s1

Procedure:
The product of step (a) was reacted with bromomethyl compound (4) as described in Example 1 and the resulting diethyl N-(5-(N-((3,4-dihydro-4-oxo-3-((pivaloyl)oxy)methyl-6-quinazolinyl)methyl)prop-2-ynylamino)thien-2-oyl-L-glutamate hydrolysed, as described in Example 1 for the corresponding benzoyl analogue, to give CB 3866.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:45][CH:46]=[CH:47][CH:48]=1)CCC>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([C:44]4[S:45][CH:46]=[CH:47][CH:48]=4)=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(OCCOc3ncc(-c4cccs4)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) (111 mg) in 1,4-dioxane (5 ml) at room temperature was added 2-(tributylstannyl)thiophene (103 mg) and bis(triphenylphosphine)palladium (II) chloride (6.5 mg) the mixture was stirred and heated to reflux for 3 hrs followed by 16 hrs. at room temperature. To the mixture was added bis(triphenylphosphine)palladium (II) chloride (6.5 mg) and the mixture was heated to reflux for a further 4 hrs. The reaction was diluted with ethyl acetate (100 ml), washed with a 10% solution of potassium fluoride in water (100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a white solid (75 mg).
Reaction SMILES: [CH2:1]([C:8]1([C:29]([OH:31])=O)[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:49])[NH:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH2:48])=[CH:43][CH:42]=1)=[NH:40])([CH3:35])([CH3:34])[CH3:33]>>[CH2:21]([O:20][C:18](=[O:19])[NH:17][C:14]1[C:13](=[O:28])[N:12]2[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:29](=[O:31])[NH:48][CH2:47][C:44]3[CH:45]=[CH:46][C:41]([C:39]([NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:49])=[NH:40])=[CH:42][CH:43]=3)[CH2:9][CH2:10][C:11]2=[N:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Reactant: O=C(Nc1cnc2n(c1=O)C(Cc1ccccc1)(C(=O)O)CC2)OCc1ccccc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)C2(Cc3ccccc3)CCc3ncc(NC(=O)OCc4ccccc4)c(=O)n32)cc1

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 21b (50 mg, 0.119 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 77 mg (quantitative) of intermediate 21c.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]OS(C)(=O)=O)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:27])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:35]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O.[ClH:48]>CN(C=O)C.CCOCC>[OH2:14].[ClH:48].[ClH:48].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:42][CH2:43]3)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:27])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:42][CH2:43]3)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:27])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:48].[ClH:48]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CC(C)Oc1cccc(CC(=O)N2CCOC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)Oc1cccc(CC(=O)N2CCOC(CCN3CCC(N4CCCCC4)CC3)(c3ccc(F)c(F)c3)C2)c1
Temperature: 70 °C

Procedure:
A mixture of 1.3 g of the compound obtained in step C of EXAMPLE 71 and 1.1 g of 4-(piperid-1-yl)-piperidine in 4 ml of DMF is heated at 70° C. for 4 hours. After cooling to RT, the reaction mixture is poured into iced water and extracted with AcOEt, the organic phase is washed with 1N NaOH solution and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (90/10; v/v) as the eluent. The product obtained is taken up with a saturated solution of hydrochloric acid in ether and the precipitate formed is wrung to give 0.49 g of the expected product. M.p.=270° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH2:9]([NH2:11])[CH3:10].C(O)(=O)C.[OH-].[Na+]>O.CO>[CH2:9]([NH:11][CH2:2][CH2:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)[CH3:10]
Reactant: CCN
Reactant: C=Cc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCNCCc1cnccn1
Temperature: 70 °C
Yield: 81 %

Procedure:
A mixture of 21.2 g (0.2 mole) of vinylpyrazine, 18.0 g (0.4 mole) of ethylamine, 6.0 g (0.1 mole) of acetic acid and 60 ml methanol was placed in a pressure bottle and heated at 70° C. for 24 hours. After removing the methanol, the residue was made basic with 8.0 g (0.2 mole) of sodium hydroxide in 80 ml of water and extracted with several portions of chloroform. After removing the chloroform, the residue was distilled to give 24.5 g of β-ethylaminoethylpyrazine, b.p. 70°-72° C. at 0.5 mm Hg, nD25 =1.5103.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH3:10])[CH:8]=1)([O-])=O.[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[CH2:28][CH:27]([NH:33][CH:34]([CH2:38][CH2:39][CH3:40])[C:35](O)=[O:36])[CH2:26][CH2:25]2>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([CH:9]([N:7]2[CH:8]=[C:4]([NH:1][C:35](=[O:36])[C@@H:34]([NH:33][CH:27]3[CH2:26][CH2:25][C:24]4[C:29](=[C:30]([F:32])[CH:31]=[C:22]([F:21])[CH:23]=4)[CH2:28]3)[CH2:38][CH2:39][CH3:40])[N:5]=[CH:6]2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CC(c1ccc(C(F)(F)F)cc1)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)c2ccc(C(F)(F)F)cc2)cn1

Procedure:
4-Nitro-1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazole was reduced and then coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 521.5 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:21])([F:20])[F:9])=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1cnc(I)nc1
Product: FC(F)(F)c1ccccc1-c1ncc(Br)cn1
Yield: 52 %

Procedure:
Obtained (52% yield) following the procedure described in Intermediate 21, starting with 5-bromo-2-iodopyrimidine and 2-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Br:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[Br:24])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:27]([Mg]Br)[CH3:28]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([Br:24])=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=4[Br:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([OH:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1cc(Br)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Br)cc(OC)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
To a solution of 9-chloro-1-(2,6-dibromo-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (80.0 mg, 0.160 mmol) in tetrahydrofuran (3.2 mL) was added dropwise ethylmagnesium bromide (3 M solution in diethyl ether, 0.107 mL, 0.321 mmol) at 0° C., and the mixture was stirred at 0° C. for 5 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (78.0 mg, 0.147 mmol, 92%).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[ClH:12].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:12].[C:3]([CH:2]([N:26]1[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[OH:13])[CH2:28][CH2:27]1)[CH3:11])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=C(Cc1ccccc1O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccccc1)N1CCN(C(=O)Cc2ccccc2O)CC1

Procedure:
A mixture of 2-bromo-1-phenylpropan-1-one (3 mmol), N-(2-hydroxy-phenyl acetyl)piperazine hydrochloride (2.5 mmol) and K2CO3 (8.75 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-18), 0.65 g (67%), M+ 353.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=O)[CH2:6][CH2:7][O:8][CH3:9].CO.C([O-])=O.[NH4+].[BH3-]C#[N:20].[Na+]>Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([NH2:20])[CH2:6][CH2:7][O:8][CH3:9]
Reactant: COCCC(=O)CC(=O)OC
Reactant: [BH3-]C#N
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COCCC(N)CC(=O)OC
Yield: 101.1 %

Procedure:
Methyl-5-methoxy-3-oxovalerate (10 g, 62.5 mmol) was added to methanol (200 ml) followed by ammonium formate (39.4 g, 620 mmol) and NaBH3CN (3.9 g, 46 mmol) at 25° C. After 24 h the methanol was removed in vacuo to leave a white mass. Methylene chloride was added and the mixture filtered. The methylene chloride was evaporated resulting in an oil which was dissolved in 1N HCl (200 ml) and extracted with ether (100 ml). The ether layer was discarded and the aqueous layer was made basic using solid K2CO3. The product was extracted into methylene chloride dried over Na2SO4 and evaporated to give methyl-5-methoxy-3-aminovalerate (7.5 g). 1H NMR (d6-DMSO) δ 1.25 (m, 3H) 1.66 (m, 2H), 1.86 (bs, 2H), 2.9 (M, 2H), 3.33 (s, 3H), 3.49 (M, 2H), 3.7 (s, 3H); MS (FAB) m/z 161.2 (MH+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].BrCCCC.O>CCCCCC.CCOCC>[CH2:6]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1CO
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCBr
Solvent: O
Product: CCCCCc1ccccc1CO
Temperature: 24 °C
Reaction time: 16 h

Procedure:
245 ml of a 1.6 molar butyllithium solution in hexane is instilled in a solution of 20.0 g of 2-methylbenzyl alcohol in 185 ml of ether under argon, so that the temperature does not exceed 10° C. Then, it is refluxed for 5 hours, allowed to cool off to 24° C., 22.4 g of 1-bromobutane is instilled and it is stirred for 16 hours at 24° C. The reaction mixture is added to 100 ml of water and extracted three times with 100 ml of ether each. The organic phase is washed with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with hexane/0-30% of ethyl acetate. 20.1 g o the title compound is obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[C:13]1([C:19]2[C:23]([CH:24]=O)=[C:22]([CH3:26])[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[CH:24][C:23]1[C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:20][O:21][C:22]=1[CH3:26])[CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: Cc1onc(-c2ccccc2)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC(=Cc1c(-c3ccccc3)noc1C)C2=O
Yield: 48.7 %

Procedure:
5-Methoxy-1-indanone (1 g, 6.2 mmol) and 3-phenyl-5-methyl-4-isoxazolecarbaldehyde (1.14 g, 6.2 mmol) were dissolved in EtOH (30 ml) and NaOH(4 drops of a 4M solution in water) was added. The reaction mixture was heated to reflux for 17 h. The reaction mixture was cooled and filtered to obtain the title compound as a yellow solid (1.0 g, 49%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH:10]=O>CO.[Pd].O>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1]
Reactant: COC(C=O)OC
Reactant: CC(C)CCN
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(CNCCC(C)C)OC
Reaction time: 3 h

Procedure:
A solution of 3-methylbutan-1-amine (1.33 mL) and 2,2-dimethoxyacetaldehyde (1.73 mL) in MeOH (10 mL) was added to palladium on carbon (0.366 g) in water (0.5 mL) at 25° C. The mixture of was hydrogenated under 5 bar at 25° C. for 3 h. The reaction mixture was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)-3-methylbutan-1-amine (1.8 g) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.5 Hz, 1H), 3.39 (s, 6H), 2.74 (d, J=5.6 Hz, 2H), 2.65-2.59 (m, 2H), 1.62 (septet, J=6.7 Hz, 1H), 1.44-1.33 (m, 2H), 0.90 (d, J=6.7 Hz, 6H)