Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH:21](=[C:16]1/[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14](=[O:19])[NH:15]/1)\[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N/C(=C\c3ccccc3)C2=O)cn1
Yield: 47.6 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol), benzaldehyde (140 mg, 1.3 mmol), and sodium acetate (205 mg, 2.5 mmol), in glacial acetic acid (3 mL) were irradiated in the microwave reactor for 7 hours at 185° C. Upon cooling the mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×, 50 mL). The combined organic extracts were washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate, filtered and concentrated. the solid product was triturated with ethyl acetate/hexanes (1/1) and dried under high vacuum to afford (Z)-5-benzylidene-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (173 mg, 48%) as a light yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 2.14 (s, 3H), 2.40 (s, 3H), 6.59 (s, 1H), 5.20 (s, 2H), 7.33-7.40 (m, 3H), 7.66 (s, 2H), 7.81 (s, 1H), 8.21 (s, 1H), 11.01 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.34 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>CN(C=O)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>[CH3:25][C:24]([CH3:27])([O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1)[CH3:26]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 75 °C
Yield: 63.6 %

Procedure:
A solution of benzyl 2-(4-bromophenyl)acetate (33.5 g, 0.11 mol), t-butyl acrylate (31.6 mL, 0.22 mol) and triethylamine (85 mL, 0.64 mol) in DMF (1000 mL) was deoxygenated with argon, whereupon bis(triphenylphosphine)palladium dichloride (5.1 g, 8.3 mmol) was added. After heating at 75° C. for 12 hours the solvent was removed in vacuo providing a brown residue that was purified by chromatography on silica gel using a mixture of hexanes and ethyl acetate (9:1) to give benzyl (E)-2-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]acetate as a pale yellow oil (23.3 g, 0.07 mol) in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([NH:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>COCCOC>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:31][CH2:30][CH2:29][NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]=1[CH3:16]
Reactant: NCCNc1ccccc1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Solvent: COCCOC
Product: Cc1c(NCCNc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-methyl-pyrimidin-4-yl ester and N-phenylethylenediamine in DME. ES-MS m/e (%): 310 (M+H+, 100).
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][NH:24][CH2:23][CH2:22]4)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].I[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC#N.CCOC(C)=O>[N:1]1([C:7]2[O:8][C:9]([C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH2:25][N:24]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:23][CH2:22]4)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CI
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1oc(N2CCCCC2)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CN1CCc2cc(NC(=O)c3oc(N4CCCCC4)nc3C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 54 %

Procedure:
To a suspension of compound 154 (0.098 g, 0.25 mmol) and K2CO3 (0.5 g) in CH3CN (5 mL) was added ethyl iodoacetate (0.036 mL). After 19 h of stirring at RT, the reaction mixture was diluted in EtOAc (50 mL) and filtered. The fitrate was washed with sat NaHCO3 (2×50 mL), dried over Na2SO4, filtered, and concentrated. The crude materials were purified by prep-TLC using 25% CH3CN in CH2Cl2 as eluents to yield compound 155 as a white solid (0.064 g, 54% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.47 (d, 1H, J=2.2 Hz), 7.41 (dd, 1H, J=8.0, 2.2 Hz), 7.02 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J=7.3 Hz), 3.66 (s, 2H), 3.61 (m, 4H), 3.41 (s, 2H), 2.80 (s, 4H), 1.61 (m, 6H), 1.21 (t, 3H, J=7.3 Hz); LCMS (ESI) Rt=3.21 min, [M+1]+ 481.3.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:13])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(OCC)(=O)C>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:14][C:15]([NH:13][C:4]1[S:5][C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:2]([CH3:1])[N:3]=1)=[O:16])[CH3:22]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1nc(N)sc1-c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Reaction time: 8 h

Procedure:
A stirred solution of 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (prepared according to the method described in European patent specification EP 117082 A2) (0.068 g, 3.56 mmol) in DMF (5 ml) is treated with ethyl isocyanatoacetate (0.043 ml, 3.916 mmol) and the solution is stirred overnight. The solvent is removed in vacuo and the crude product is partitioned between ethyl acetate (50 ml) and water (50 ml). The layers are separated and the aqueous portion is extracted with ethyl acetate (2×50 ml). The combined organic portions are washed with water, dried (MgSO4), filtered and concentrated in vacuo to yield an oil. Trituration with ethyl acetate yields the titled compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][C:11](B(O)O)=[CH:12][C:7]=3[NH:6][C:5]2=[O:16])[CH2:3][CH2:2]1.Br[CH:18]=[C:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:20]1=2.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][C:11]([CH:18]=[C:19]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:20]4=5)=[CH:12][C:7]=3[NH:6][C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cc(B(O)O)ccc2n1C1CC1
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccccc4COc4cc(F)ccc43)ccc2n1C1CC1
Yield: 29.7 %

Procedure:
Following procedures essentially as described in Example 219, mix 1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid (120 mg, 0.55 mmol) (prepared essentially as described in Preparation 36), 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (E and Z mixture, 177 mg, 0.58 mmol), 2N Na2CO3 (0.7 mL), dioxane (8 mL) and (Ph3P)4Pd (38 mg, 0.033 mmol). Purify the crude product by column chromatography using THF/hexane to give 65 mg title compound as a gray powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=O)[O:30]C(C)(C)C)[O:24][C:23]2=[O:36])[CH:12]=[CH:13][C:14]=1[N:15]1[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl:37][CH:38]([Cl:44])C(OCC)=O>ClC(Cl)C>[Cl:37][CH:38]([Cl:44])[C:29]([NH:28][CH2:27][CH:25]1[O:24][C:23](=[O:36])[N:22]([C:11]2[CH:12]=[CH:13][C:14]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[C:9]([F:8])[CH:10]=2)[CH2:26]1)=[O:30]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=CN(c2ccc(N3CC(CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Reaction time: 1.5 h

Procedure:
TFA (0.75 mL) is added to a solution of the carbamate from Step 6 of Example 3 (100 mg, 0.247 mmol) in dichloroethane (3.0 mL). This solution is stirred for 1.5 h., and the solvent is removed under vacuum. The residue is dissolved in MeOH (4.0 mL). TEA (105 mg, 1 mmol) is added to the mixture, followed by adding ethyl dichloroacetate (77 mg, 0.49 mmol). The mixture is stirred at r.t. for 16 h. Solvent is removed under vacuum, and the crude product purified by silica gel column chromatography (gradient 1% to 2% MeOH in DCM). MS (m/z): 417 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (t, J=5.5 Hz, 1H), 7.79 (d, J=14.3 Hz, 1H), 7.69–7.48 (m, 3 H), 6.67 (s, 1H), 5.17 (d, J=7.7 Hz, 1H), 5.05–4.99 (m, 1H), 4.35 (t, J=9.1 Hz, 1H), 4.06 (t, J=7.7 Hz, 3H), 3.93 (dd, J=6.0 and 9.3 Hz, 1H), 3.74–3.72 (m, 2H), 3.51–3.49 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:26])=[CH:6][CH:7]=[C:8]([CH3:25])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:26][C:5](=[CH:6][CH:7]=[C:8]([CH3:25])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CO
Reaction time: 4 h

Procedure:
A solution of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoic acid ethyl ester (1.85 g, 5 mmol) in 25 ml of anhydrous THF is cooled to -10° C. and 0.19 g (5 mmol) of LAH is added in portions. The resulting mixture is stirred for 4 hours and quenched carefully with 0.4 ml of water. The mixture is suction-filtered and the residue thoroughly washed with ether. The combined filtrate and washings are dried (MgSO4) and evaporated under reduced pressure to give the crude product. Purification by HPLC (4% ethylacetate in hexane on silica gel column) gives the pure desired product.
Reaction SMILES: CN.[CH3:3][N:4](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[C:33]1[CH:34]=[N:35][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]([N:50]([CH2:52][C:53]([OH:55])=O)[CH3:51])=[O:49])[CH:46]=3)[C:41]([S:56][CH3:57])=[CH:40]2)=[N:37][CH:38]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[C:33]1[CH:38]=[N:37][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]([N:50]([CH3:51])[CH2:52][C:53]([NH:4][CH3:3])=[O:55])=[O:49])[CH:46]=3)[C:41]([S:56][CH3:57])=[CH:40]2)=[N:35][CH:34]=1
Reactant: CSc1cn(-c2ncc(-c3cc(C)ccc3F)cn2)c2cc(C(=O)N(C)CC(=O)O)ccc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Product: CNC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1

Procedure:
Methylamine (2M in THF, 1.54 ml, 3.09 mmol) was coupled with TBTU to 304c) (0.48 g, 1.03 mmol). Light yellow solid. Yield: 0.22 g (45% of theory)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2([NH2:13])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([CH2:22][C:23](O)=[O:24])[CH2:15]2>>[N:14]12[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]1)[CH:16]([CH2:22][C:23]([NH:13][C:10]1([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[CH2:12][CH2:11]1)=[O:24])[CH2:15]2
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: CC(C)c1cccc(C2(N)CC2)c1
Product: CC(C)c1cccc(C2(NC(=O)CC3CN4CCC3CC4)CC2)c1
Yield: 13.6 %

Procedure:
Using general procedure I, 1-(3-isopropyl-phenyl)-cyclopropylamine (278 mg, 1.58 mmol) and (1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (267 mg, 1.58 mmol) gave the title compound as a white solid (70 mg, 14%). 1H NMR (400 MHz, CD3OD) δ 7.16 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.97 (dd. J=19.2, 7.6 Hz, 2H), 3.16-3.23 (m, 1H), 2.79-2.97 (m, 5H), 2.51-2.58 (m, 1H), 2.23-2.41 (m, 3H), 1.83-1.92 (m, 1H), 1.68-1.81 (m, 3H), 1.54-1.62 (m, 1H), 1.15-1.25 (m, 10H) ppm. 13C NMR (400 MHz, CD3OD) δ 173.6, 148.5, 142.4, 127.8, 123.6, 123.1, 122.0, 73.0, 53.1, 46.6, 45.9, 39.3, 34.1, 32.3, 28.1, 26.4, 24.4, 19.7, 16.8 ppm. Purity: 96.9% HPLCMS (210 nm); retention time 2.55 min; (M+1) 327.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15]O)[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH2:15][F:27])[CH2:12][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CF)CN(C(=O)OCc2ccccc2)C1
Yield: 45 %

Procedure:
A solution of cis (+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-(hydroxymethyl)piperidine-1-carboxylate (1 eq.), perfluorobutanesulfonylfluoride (2 eq.), triethylamine-HF (4 eq.) and triethylamine (6 eq.) in tetrahydrofuran at a concentration of 0.16 M was stirred for 36 hours. Upon dilution with ethyl acetate (50×) the solution was washed with 1N HCl, NaHCO3(sat.) and brine, was dried over MgSO4, filtered, concentrated and purified by column chromatography (25-40% ethyl acetate/hexanes) to yield cis (+/−)-benzyl 3-(tert-butoxycarbonylamino)-5-(fluoromethyl)piperidine-1-carboxylate (45% yield). LCMS (m/z): 267.1 (MH+); LC Rt=4.23 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[OH:28][CH2:29][CH2:30][CH2:31][NH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1>CN(C=O)C>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:32]([CH2:31][CH2:30][CH2:29][OH:28])[CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:35][CH2:34]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCCO)CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl 4-[(3-hydroxypropyl)amino]-piperidine-1-carboxylate (Yokoyama et al., Bioorg. Med. Chem. 2008, 16, 7968) in DMF gave tert-butyl 4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylate: 1H NMR (DMSO-d6) (rotamers) δ 7.99 and 7.90 (2d, J=8.4, 8.5 Hz, 1H), 7.78 and 7.70 (2t, JHF=52.9, 52.3 Hz, 1H), 7.42 and 7.37 (2t, J=8.3 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.71-4.64 and 4.58-4.47 (2m, 2H), 4.13-4.04 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.79 and 3.69 (2br m, 8H), 3.60-3.46 (m, 4H), 2.82-2.79 (m, 2H), 1.79-1.62 (m, 6H), 1.42 (br s, 9H); Anal. Calcd. for C24H40F2N8O5: C, 56.3; H, 6.5; N, 18.1. Found: C, 56.4; H, 6.7; N, 18.0%.
Reaction SMILES: Cl[C:2]1[C:19]2[C:6](=[C:7]3[C:16](=[CH:17][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9](=[O:21])(=[O:20])[NH:8]3)[N:5]=[CH:4][CH:3]=1.[NH3:22]>CO>[O:20]=[S:9]1(=[O:21])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[C:7](=[C:6]3[C:19](=[CH:18][CH:17]=2)[C:2]([NH2:22])=[CH:3][CH:4]=[N:5]3)[NH:8]1
Reactant: N
Reactant: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Solvent: CO
Product: Nc1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Yield: 20 %

Procedure:
In a similar fashion using route 48 general procedure 114, 1-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 305 (90 mg, 0.28 mmol), 7M NH3 in MeOH (5 ml) gave the title compound (17 mg, 20%) after purification by column chromatography eluting with chloroform/MeOH (98:2:1 drop NH3).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[C:26]([N:27]=3)=[CH:25][CH:24]=[C:23]([C:28]3([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:30][CH2:29]3)[N:22]=4)=[C:15]([F:37])[CH:14]=2)[CH2:10][C@H:9]1[C:38]([OH:40])=[O:39])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[F:37][C:15]1[CH:14]=[C:13]([C@@H:11]2[CH2:12][NH:8][C@H:9]([C:38]([OH:40])=[O:39])[CH2:10]2)[CH:18]=[CH:17][C:16]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:30]1)[N:22]=2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1

Procedure:
To a slurry of (2S,4R)-1-(tert-butoxycarbonyl)-4-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid (0.091 g, 0.16 mmol) in 2 mL DCM was added trifluoroacetic acid (0.13 mL, 1.6 mmol) to give a yellow solution. Upon completion the reaction mixture was concentrated in vacuo and the material was triturated with MTBE to give (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid trifluoroacetic acid salt. MS (ESI) m/z: Calculated: 459.1; Observed: 459.8 (M++1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22-8.36 (m, 2 H), 7.57 (d, J=13.1 Hz, 1 H), 7.27-7.49 (m, 8 H), 7.05 (d, J=8.6 Hz, 1 H), 4.42 (dd, J=10.0, 7.6 Hz, 1 H), 3.59-3.81 (m, 2 H), 3.24-3.34 (m, 1 H), 2.72-2.85 (m, 1 H), 2.06-2.22 (m, 1 H), 1.62-1.74 (m, 2 H), 1.34-1.45 (m, 2 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](N2CCN(C3C(Cl)=CN=CC=3Cl)CC2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:25]C1C=NC=C(Cl)C=1N1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:25])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)N1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Product: O=S(=O)(Cl)c1cccc(Cl)c1
Yield: 66 %

Procedure:
In an analogous manner to Example 1F, step 1Q 1-[(3-chlorophenyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43 mmol) and 3-chlorobenzene sulfonyl chloride (66% yield).
Reaction SMILES: [Mg].[CH:2](I)([CH3:4])[CH3:3].CO[C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>C(OCC)C>[CH:2]([C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: COc1cccc(C#N)c1OC
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C#N)c1C(C)C
Temperature: 0 °C
Yield: 24.9 %

Procedure:
To a mixture of 2.76 g (0.115 mol) of magnesium in 75 mL of diethylether, was slowly added 24.31 g (0.143 mol) isopropyl iodide. The resulting reaction mixture was allowed to react until all of the magnesium was consumed. Then, a solution of 15.0 g (0.92 mol) of 2,3-dimethoxy benzonitrile in 75 mL of diethylether was added over ninety minutes. The resulting reaction mixture was reacted overnight at room temperature and then refluxed for four hours. The resultant reaction mixture was then cooled to 0° C., and the top layer was decanted into saturated ammonium chloride and ice. The resultant layers were separated and the organic layer was washed sequentially with a dilute sodium hydroxide solution, water, and a dilute hydrochloric acid solution, dried over sodium sulfate, filtered and then concentrated to provide an orange oil. This oil was distilled under reduced pressure (5 inch vigreux column; 0.2 mm Hg) to provide 6.25 g of an orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN1C(=O)CCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:7]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(c2cc(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)ccn2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
Compound 39 (391 mg, 1.00 mmol) was dissolved in NMP (10 mL), and 1-methylpiperazine (1.11 mL, 10.0 mmol) was added thereto, followed by stirring overnight at 150° C. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1) to afford the entitled Compound 41 (22.2 mg, 5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[S:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:3][CH:4]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C(Cl)CCCCCCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
8-Bromooctanoic acid (2 g, 8.90 mmol, 1 equiv) was stirred in CH2Cl2 (15 mL) under N2 atmosphere and thionyl chloride (784 μL, 10.68 mmol, 1.2 equiv) added followed by DMF (few drops). The solution was stirred for 16 h and concentrated in vacuo to give 8-bromooctanoyl chloride (2.04 g, 95%) as a yellow oil which was used without further purification. Thiourea 4 (600 mg, 1.84 mmol, 1 equiv.) was stirred in CH2Cl2 (15 mL) under N2 atmosphere. 8-Bromooctanoyl chloride (532 mg, 2.02 mmol, 1.2 equiv.) was added, followed by triethylamine (256 μL, 1.84 mmol, 1 equiv.). The beige suspension was stirred at rt for 16 h and diluted with CH2Cl2 (20 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×20 mL), 10% aqueous sodium hydroxide (1×20 mL), and saturated brine (1×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 8-bromo-octanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (579 mg, 59%) as a yellow oil.