Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)=[CH2:23]>C(Cl)Cl>[CH:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][Br:1])=[CH:26][CH:25]=1)=[CH2:23]
Reactant: C=Cc1ccc(CO)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
Bromine (16.4 g, 103 mmol) was slowly added to a solution of triphenylphosphine (28.87 g, 110.1 mmol) in CH2Cl2 (260 mL) at 0° C. After 10 minutes, 4-vinylbenzyl alcohol (12.5 g, 93.3 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with water (1×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was triturated with petroleum ether (3×), and the ethereal solution was concentrated in vacuo. The residue was purified by flash chromatography (hexanes) to afford 4-vinyl-benzyl bromide (6.23 g). 1H NMR (400 MHz, CDCl3) δ 7.32-7.45 (m, 4H), 6.72 (dd, 1H), 5.77 (d, 1H), 5.28 (d, 1H), 4.50 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:17]1([NH:20][CH3:21])[CH2:19][CH2:18]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:15])[N:20]([CH:17]1[CH2:19][CH2:18]1)[CH3:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CNC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (R)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (788 mg, 1 eq.), cyclopropyl-methyl-amine hydrochloride (478 mg, 1.2 eq.), HOBt (7.48 mg, 1.5 eq.), EDAC (1.05 g, 1.5 eq.) and TEA (1.5 mL, 3 eq.) in DMF (15 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was washed with brine, dried, concentrated, purified on a silica gel column to give (R)-2-(cyclopropyl-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH3:26])[CH2:19][CH3:20])=[N:7][N:6]=[CH:5]2
Reactant: CCN(CC)CCN
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCNc1nncc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Bromo-1-chlorophthalazine (0.22 g, 0.91 mmol) was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (0.25 g, 1.81 mmol) and N1,N1-diethylethane-1,2-diamine (0.25 mL, 1.81 mmol) were added. The reaction mixture was heated to 80° C. for 5 h, cooled to ambient temperature and stirred for 16 h. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3× with 20 mL of sodium bicarbonate (saturated, aqueous) and once with aqueous brine, separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 323(M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][C:11](=O)[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:21][OH:22]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][C:11](=[N:21][OH:22])[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)N1C2COCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)N1C2COCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 9-isopropyl-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (CAS no: 99189-30-7)(1.25 g, 6.82 mmol) in ethanol (40 mL) and pyridine (0.8 mL, 10.2 mmol) with hydroxylamine hydrochloride (0.5 g, 7.23 mmol) was refluxed for 6 h. Cooled to 23° C., evaporated all volatiles, partitioned the residue between dichloromethane and sodium carbonate solution, reextracted the aqueous layer with tetrahydrofuran/ethyl acetate, all combined organic layers were dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a dark brown solid. (1.0 g, 74%); MS: m/e=199.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][C:18]2[NH:19][CH:20]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:22]=2)[CH2:14][S:13]1.[CH2:27](Br)[CH:28]([CH3:30])[CH3:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C@@H:15]([CH2:17][C:18]2[NH:19][CH:20]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:22]=2)[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](Cc2nc(CC(C)C)c[nH]2)CS1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](Cc2nc(CC(C)C)c[nH]2)N1CC(C)C

Procedure:
(L)-Histidinol was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-(1-(isobutylimidazoly)methyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(1-(isobutylimidazolyl)methyl)-1,3-thiazolidine.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=4[N:13]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([N:8]3[C@@H:1]4[C@@H:6]([CH2:5][CH2:4][N:3]([C:38]([C:37]5[C:41]([N:45]6[N:49]=[CH:48][CH:47]=[N:46]6)=[CH:42][CH:43]=[CH:44][C:36]=5[F:35])=[O:39])[CH2:2]4)[CH2:7]3)=[N:13][C:12]=2[CH:14]=1
Reactant: Clc1ccc2oc(N3C[C@@H]4CCNC[C@@H]43)nc2c1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC[C@H]2CN(c3nc4cc(Cl)ccc4o3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 2-((1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl)-5-chlorobenzo[d]oxazole (Intermediate 32) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C22H18ClFN6O2, 452.88; m/z found 453.0 [M+H]+. 1H NMR (CD3OD): 8.04-7.74 (m, 2H), 7.67-7.24 (m, 4H), 7.15-6.64 (m, 2H), 5.04-4.23 (m, 3H), 4.20-3.35 (m, 4H), 3.20 (br s, 1H), 2.37-1.88 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2Cc2ccc([N+](=O)[O-])cc2)c1
Yield: 10 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-bromomethyl-4-nitro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-(4-nitro-benzyl)-9H-purin-6-ylamine: Yield 10%, 1H NMR (DMSO-d6) δ 8.20 (s, 1H), 8.04 (d, J=6.8 Hz, 2H), 7.57 (bs, 2H), 7.30 (d, 6.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.70 (dd, J=9.2, 3.2 Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 5.52 (s, 2H), 3.71 (s, 3H), 3.52 (s, 3H); LC-MS [M+H]+ 439.1.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36]C(=O)OC(C)(C)C)[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC(CN)CC5)n4)n[nH]c3cn2)cn1
Yield: 63 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl piperidin-4-ylmethylcarbamate were reacted and the product was deprotected to give 182 as a white solid (63% over two steps). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.50 (d, J=12.1 Hz, 2H), 3.91 (s, 3H), 2.99 (t, J=12.5 Hz, 2H), 2.53-2.44 (m, 4H), 1.92-1.74 (m, 3H), 1.58 (s, 1H), 1.31-1.18 (m, 2H). LC/MS: m/z 389.2 [M+1]
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].O.[NH2:21]N>CCO>[CH3:7][C:6]([C:5]1[NH:21][N:2]=[CH:3][CH:4]=1)([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:17]
Reactant: NN
Reactant: CN(C)C=CC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccn[nH]1
Temperature: 50 °C

Procedure:
A mixture of 1-dimethylamino-4-methyl-4-(4-nitro-phenyl)-pent-1-en-3-one (0.36 g, 1.4 mmol.) and hydrazine hydrate (1.0 g, 6.25 mmol.) in EtOH was heated at 50° C. for 3 h. The mixture was concentrated, and the residue was diluted with H2O and EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the titled compound as a yellow solid. MS: 232 (M+1) Calc'd for C12H14N3O2—232.10.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][CH2:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:23]=3)[C:19]([Cl:37])=[CH:18][N:17]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:44][O:45][CH2:46][CH2:47]OS(C1C=CC(C)=CC=1)(=O)=O>CS(C)=O>[Cl:37][C:19]1[C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:23]=2)=[CH:21][C:16]([NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:8][CH2:47][CH2:46][O:45][CH3:44])[CH2:10][CH2:11]2)=[N:17][CH:18]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3F)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: COCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3F)c(Cl)cn2)CC1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-3-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine trifluoroacetate (30 mg, 0.055 mmol) and sodium carbonate (23 mg, 0.22 mmol) in DMSO (0.75 ml) was added p-toluenesulfonic acid 2-methoxyethyl ester (15 mg, 0.066 mmol). The mixture was stirred at 85° C. for 20 hr in a sealed microwave vial. The cooled reaction mixture was filtered. The filtrate was purified by reverse phase HPLC and lyophilized to give 5.0 mg of 5′-chloro-3-fluoro-N2′-(trans-4-(2-methoxyethylamino)cyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 492.2 (MH+), retention time=0.57 min.; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10-1.46 (m, 6H) 1.64-1.74 (m, 2H) 1.86 (br. s., 2H) 1.95-2.09 (m, 2H) 2.09-2.26 (m, 2H) 2.58 (br. s., 1H) 2.88 (t, J=5.09 Hz, 2H) 3.17 (t, J=6.26 Hz, 2H) 3.29-3.45 (m, 5H) 3.53 (t, J=5.09 Hz, 3H) 4.00 (dd, J=11.35, 3.52 Hz, 2H) 4.34-4.47 (m, 1H) 4.54-4.68 (m, 1H) 6.35-6.48 (m, 2H) 7.31 (t, J=8.80 Hz, 1H) 8.11 (s, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[C:4]([NH2:19])=[CH:3][CH:2]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(OC(C)=O)=O>CC(CC)=O>[C:20]1([NH:26][C:27]([NH:19][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[C:7]2[O:18][C:16](=[O:17])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1C(=O)O
Solvent: CCC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccccc1-c1nc2ccccc2c(=O)o1
Temperature: 80 °C

Procedure:
A 250 ml three-neck bottle was charged under room temperature with 12.8 g [0.05 mol] anthranoylanthranilic acid and 100 ml methylethylketone. Under stirring 5.95 g [0.05 mol] phenylisocyanate was added and heated for about 4 hours under reflux about 80° C.). After this the suspension was cooled down to about. 40° C. Then 40 ml acetanhydrid was added and then heated additionally for 3 hours. After cooling down to 10° C. the precipitate was sucked off, washed with acetone and dried at 50° C. under normal pressure.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OCC)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>C(O)C>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([NH:27][NH2:28])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: CCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A solution of 13B (750 mg, 2.134 mmol) in ethanol (5 mL) was treated with hydrazine.H2O (1.036 mL, 21.34 mmol), stirred at 80° C. for 2 h. No product was observed so more hydrazine.H2O (1.036 mL, 21.34 mmol) was added, and the solution was stirred at 150° C. in sealed tube overnight. Upon cooling, water was added and the resulting white solid was collected by filtration, washed with water and air dried to provide 14A (754 mg, >quantitative yield) as a white solid. MS (ES): m/z=338.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.16-7.40 (m, 10H); 6.58 (br. s, 1H); 3.76 (br. s, 2H); 3.55 (s, 4H); 2.42-2.51 (m, 1H); 1.79-1.97 (m, 5H); 1.25-1.42 (m, 4H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([CH2:63][CH2:64][NH2:65])[CH2:62][CH2:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH2:64][CH2:63][N:58]5[CH2:62][CH2:61][CH2:60][CH2:59]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(pyrrolidin-1-yl)ethanamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 1H) 1.38 (m, 2H) 1.65 (t, J=13.1 Hz, 3H) 1.79-1.92 (m, 6H) 2.03 (m, 2H) 3.08 (m, 2H) 3.33 (s, 3H) 3.35 (d, J=5.8 Hz, 2H) 3.61 (m, 4H) 3.96 (s, 3H) 4.12 (t, J=13.0 Hz, 2H) 4.40-4.58 (m, 1H) 7.53 (d, J=8.6 Hz, 1H) 7.56 (s, 1H) 8.22 (s, 1H) 8.24 (d, J=1.3 Hz, 1H) 8.29 (d, J=7.8 Hz, 1H) 8.7 (dd, J=10.1, 1.3 Hz, 1H). [M+H] calc'd for C28H37F2N7O3 558. found 558.
Reaction SMILES: [BH4-].[Na+].O.[CH3:4][C:5]1([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([CH3:11])=[CH:7][O:6]1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.CC(C)=O>[CH3:4][C:5]1([CH2:12][OH:13])[CH2:10][CH2:9][C:8]([CH3:11])=[CH:7][O:6]1
Reactant: CC1=COC(C)(C=O)CC1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: CC1=COC(C)(CO)CC1
Reaction time: 0.5 h

Procedure:
3.12 g of sodium borohydride was added to a rapidly stirred mixture of 140 ml of ether and 70 ml of water under a nitrogen atomosphere. To the resulting solution, a solution of 21.0 g of 3,4-dihydro-2,5-dimethyl-2H-pyran-2-carboxaldehyde (U.S. Pat. No. 2,479,283) in 42 ml of ether was added drop by drop. After 30 minutes, 21 ml of acetone was added. After 5 more minutes, the mixture was doubled in volume with a saturated solution of potassium carbonate and extracted with ether. The extract was washed with saturated sodium chloride solution, dried (sodium sulfate) and stripped of solvent to give 3,4-dihydro-2,5-dimethyl-2H-pyran-2-methanol (12A), as a pale green liquid, b.p.: not determined.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([O-])([O-])=[O:13].[K+].[K+]>CO>[Br:1][C:2]1[C:3](=[O:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([OH:13])[CH:5]=2
Reactant: O=C([O-])[O-]
Reactant: O=C1C(Br)=Cc2ccccc21
Agent: [K+]
Solvent: CO
Product: O=C1C(Br)=Cc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1 to 1.2 eq of the 2-bromo-1H-indenone prepared in Step 4 is dissolved in MeOH, and then K2CO3 (1 to 2 eq) is added thereto. The resulting mixture is stirred at room temperature for 2 to 7 h, to obtain the 2-bromo-6-hydroxy-1H-indenone of formula 8 in which acetyl group is removed.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([N:21]5[CH2:25][CH2:24][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]5)[N:19]=4)[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:36]I>O1CCCC1>[CH3:36][N:26]([C@@H:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[C:20]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:16][CH:17]=2)[CH2:22]1)[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a cooled (0° C.) solution of (R)-tert-butyl 1-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrrolidin-3-ylcarbamate (111 mg, 0.249 mmol) in tetrahydrofuran (2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 15 mg, 0.37 mmol). After 30 minutes at 0° C., a solution of methyl iodide (23 uL, 0.37 mmol) in tetrahydrofuran (0.5 mL) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature as the ice bath melted, stirred overnight, then quenched by adding water (1.0 mL). The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was diluted with ethyl acetate (100 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform/acetone (2-20%) to afford tert-butyl methyl{(3R)-1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-yl}carbamate (104 mg, 91%)
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)=[C:28]([CH:31]=3)[CH:29]=[O:30])=[N:20][CH:21]=2)=[CH:12][CH:11]=1.[F-].[Cs+].Cl.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([O:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)=[C:28]([CH:29]([OH:30])[C:3]([F:6])([F:5])[F:4])[CH:31]=3)=[N:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C=O)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C(O)C(F)(F)F)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
0.523 mL (1.05 mmol) of trimethyltrifluoromethylsilane (2M in THF) was slowly added dropwise at −10° C. to a solution of 0.39 g (0.85 mmol) of 5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]benzaldehyde (Example 14.1c) and 13 mg (0.087 mmol) of cesium fluoride in 10 mL of THF and the reaction mixture was stirred for 2 hours at −10° C. 7 mL of 1M aqueous HCl were added and the mixture was stirred. The reaction mixture was made alkaline by the addition of saturated aqueous potassium carbonate solution and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. The crude product was purified by chromatography (silica gel, EtOAc/MeOH/sat. aqueous ammonia 95:5:0.5). Yield: 25 mg (5% of theoretical); C29H28ClF3N2O2 (M=528.993); calc.: (M+H)+:529/531 (Cl); found: molpeak (M+H)+:529/531 (Cl); HPLC-MS: 5.95 minutes (method B).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[CH3:18][C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:31](O)=[O:32])=[CH:21][N:20]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:31]([C:22]2[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:24][C:19]([CH3:18])=[N:20][CH:21]=2)=[O:32])[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Product: Cc1ncc(C(=O)Nc2ccc(Cl)c(NC(=O)c3ccccc3)c2)c(-c2ccccc2)n1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.24 mmol) was used in general procedure 2 with 2-methyl-4-phenylpyrimidin-5-carboxylic acid (0.30 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-2-methyl-4-phenylpyrimidin-5-carboxamide. MS (Q1) 443.1 (M)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-nitrophenyl)butyric acid (3 g, 14 mmol) (Aldrich Chemical Company Ltd.) and 10% palladium on charcoal catalyst (0.3 g) in ethanol (100 ml) was submitted to gaseous hydrogen at 50 p.s.i., 20° C., for 30 minutes. The mixture was then filtered and concentrated. The resulting solid residue was recrystallised from isopropanol to give 4-(4-aminophenyl)butyric acid. (1.9 g, 76%) mp. 125°-127° C.