Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][C:28]=5Cl)[CH:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CN(C(=O)[C@H](NC([C:55]2[C:63]3[C:58](=NC=C(C4SC5C(=NC=CC=5Cl)C=4)N=3)[N:57](COCC[Si](C)(C)C)[CH:56]=2)=O)C2CC2)C1)#N>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][C:28]=5[N:57]5[CH2:58][CH2:63][CH2:55][CH2:56]5)[CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc4nccc(Cl)c4s3)nc12)C(=O)N1CC(C#N)C1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc4nccc(N5CCCC5)c4s3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 155 substituting 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide in step 1. MS: (M+H)+=501.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH:31]=[C:32]([C:34](Cl)=[O:35])[N:33]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[CH:31]=[C:32]([C:34]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[O:35])[N:33]=1
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: O=C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
Triethylamine (1.46 mL, 10.45 mmol) was added to a suspension of 4-piperidinone trifluoroacetate (0.76 g, 3.58 mmol) in CH2Cl2 (10 mL) and a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride in CH2Cl2 (5 mL) was added. The mixture was stirred at rt under argon for 17 h, diluted with CH2Cl2 (50 mL), washed with water (2×50 mL), dried over MgSO4, and concentrated to give 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol4-yl]carbonyl}-4-piperidinone as a yellow solid (0.96 g, 77%). MS (Electrospray) 414 (MH+), 1H NMR (300 MHz, CD2Cl2) δ 7.80 (s, 1H), 7.37-7.20 (m, 6H), 7.06-7.00 (m, 6H), 4.47 (br, 2H), 3.92 (br, 2H), 2.46 (t, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25]>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[CH:7]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccccc1C(N)=O)C(F)(F)F
Yield: 61 %

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (500 mg) and 2-aminobenzamide (1.17 g) in dimethylformamide (2.5 mL) was heated at 140° C. for 19.5 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 15 to 30% ethyl acetate-hexanes) to give 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]benzamide as a white foam (447 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C1COCC1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1>CCOC(C)=O.O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:20][CH:21]=1
Reactant: OC1CCOCC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cnc(OC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.1 %

Procedure:
Tetrahydro-2H-pyran-4-ol (200 mg) was mixed with THF (5 ml), and sodium hydride (55% suspended in oil) (120 mg) was added thereto, followed by stirring at room temperature for 5 minutes. 5-Bromo-2-chloropyrimidine (460 mg) was added to the reaction mixture, followed by stirring at room temperature. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(tetrahydro-2H-pyran-4-yloxy)pyrimidine (361 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:27])[CH3:28])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 69.5 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(2-(dimethylamino)-1-hydroxyethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (48 mg, 0.165 mmol) to afford the desired product (41 mg, 69%) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.38 (s, 1H), 8.22 (dd, J=8.8, 2.0 Hz, 1H), 8.07-7.98 (m, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.38 (s, 2H), 5.18 (dd, J=9.8, 4.3 Hz, 1H), 3.25-3.14 (m, 2H), 3.02 (s, 3H), 2.95 (s, 3H), 2.86-2.79 (m, 1H), 1.22-1.11 (m, 4H); ESI MS m/z 536 [C29H27Cl2N3O3+H]+; HPLC 95.1% (AUC), tR=11.42 min.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[C:29]([Cl:34])[N:28]=1.[OH-].[Na+].CCOC(C)=O>CC(C)=O.O.CN(C=O)C>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:31]4[CH:30]=[C:29]([Cl:34])[N:28]=[C:27]([NH2:26])[N:32]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 567 mg (1.62 mMol) of 7-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Step 6.2), 532 mg (3.24 mMol) 2-amino-4,6-dichloro-pyrimidine and 145 mg (3.62 mMol) NaOH in 5 ml acetone, 7 ml H2O and 3 ml DMF is stirred at 60° C. for 24 h. Then it is poured into water and EtOAc, the aqueous phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/EtOAc 2:1→3:2) gives the title compound: m.p.: 175° C.; MS: [M+1]+=478/480; Anal.: C,H,N,Cl.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([F:11])=[CH:9][CH:10]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)nc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-fluoropyridin-3-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (193 mg, 0.53 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (232 mg, 82%).
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15].CON(C)[C:22]([C@@H:24]1[CH2:28][S:27][C:26]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34](S(C2C=CC=CC=2)(=O)=O)[CH:33]=[CH:32]3)=[N:25]1)=[O:23]>C1COCC1.[OH-].[Na+].C(O)C>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([C:26]3[S:27][CH:28]=[C:24]([C:22]([C:10]4[CH:9]=[C:8]([O:7][CH3:6])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:23])[N:25]=3)=[CH:37][CH:36]=2)[CH:32]=[CH:33]1
Reactant: CON(C)C(=O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2csc(-c3ccc4[nH]ccc4c3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of n-BuLi (1.6 M, 1.7 mL) in 8 mL THF was added a solution of 3,4,5-trimethoxybromobenzene (2.47 mmol) in 3 mL THF under −78° C. The mixture was allowed to stir for 2 h and a solution of Weinreb amide 65a (1.24 mmol) in 3 mL THF was charged. The temperature was allowed to increase at RT and stirred overnight. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was refluxed in 1 N NaOH in 5 mL ethanol solution to obtain the deprotected compound 31 and purified by column chromatography to obtain pure compound as a light yellow solid (36.3%). 1H NMR (300 MHz, CDCl3) δ 8.36 (br, s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.92, 7.89 (dd, 1H, J=1.8, 2.7 Hz), 7.46 (d, 1H,) 7.62 (s, 2H, J=8.7 Hz), 7.29 (t, 1H, J=2.7 Hz), 6.64 (br, 1H), 3.97 (s, 6H), 3.97 (s, 3H); MS (ESI) m/z 417.1 (M+Na)+, 392.9 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>CN(C)C=O>[NH:26]1[CH:27]=[C:23]([CH2:22][C:8]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]#[N:10])[N:24]=[CH:25]1
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
As described in Example 1, 7.26 g. of 2,2-bis(4-chlorophenyl)acetonitrile, 1.33 g. of 50% sodium hydride and 2.12 g. of 4-chloromethylimidazole hydrochloride were reacted in 50 ml. of dimethylformamide. The mixture was stirred for 2 hours at 60° C. and then 21 hours at ambient temperature. The solvent was then evaporated off under vacuum and the reaction mixture was worked up as described in Example 1 to obtain 5.2 g. of the free base named above, which was converted to the maleate salt and crystallized from acetone/diethyl ether to obtain 5.73 g. of the maleate salt of the product named above, m.p. 151.5°-153° C.
Reaction SMILES: C([NH:11]CCCC[C@@H](C(O)=O)N)(OCC1C=CC=CC=1)=O.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].Cl>[OH-].[Na+]>[NH2:11][C@H:22]([C:21]([OH:28])=[O:27])[CH2:23][C:24](=[O:26])[OH:25]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 5 h

Procedure:
N6-Carbobenzyloxy-L-lysine (6.15 g) and excess maleic acid (17.6 g) were dissolved in 2 M NaOH (35 mL). The solution was refluxed for 24 hr and allowed to cool to ambient. The pH was adjusted to 3 with 6 M HCl and chilled. The mixture was filtered to remove the unreacted maleic acid which was washed with water (15 mL). The filtrate and washings were combined and evaporated. The residue was dissolved in 4% ammonium formate (120 mL) and degassed briefly. 10% Pd/C (600 mg) was added and the mixture was refluxed under Ar with stirring for 5 hr. The mixture was filtered through celite and the filtrate evaporated. The residue was dissolved in a solution of sodium hydroxide (1.3 g) and sodium carbonate (8.7 g) in dd H2O (40 mL). The final pH was adjusted to 11. This solution is added to the oxirane-derivatized resin (40 ml bed volume) prepared as described in Example 1. The mixture was stirred at 60° with mechanical stirring for 4hr and at ambient for 16 hr. The resin was collected by filtration, washed with ddH2O (6×100 mL), 10% HOAc (6×100 mL), and ddH2O (6×100 mL) or until the pH reached about 6 by litmus paper test. The C-Linked CM-Asp chelating resin was suction dried in preparation for metal loading.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: ICCC1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCC3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 2-iodoethylcyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:13]([O-])=O.[Cl-].[NH4+]>C(O)C.CN(C)C=O.[Fe]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[NH2:13]
Reactant: COc1cc2ncccc2cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2ncccc2cc1N
Yield: 84.9 %

Procedure:
A mixture of 7-methoxy-6-nitro-quinoline (5 g, 24.0 mmol), iron powder (9.8 g, 172 mmol) and ammonium chloride (9.1 g, 172 mmol) in a mixture of ethanol and water (3/1, 160 mL) was heated at reflux overnight. The resulting mixture was filtered through a CELITE™ pad, the filtrate was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc) to afford 3.551 g of 7-methoxy-quinolin-6-ylamine as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24]Br)=[O:20])([CH3:17])([CH3:16])[CH3:15].[I-].[K+]>CN(C)C=O.O>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1OCCCNC(=O)OC(C)(C)C
Reaction time: 60 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-methoxysalicylate (11.48 g, 63 mmol) in dimethylformamide (30 mL) was added solid K2 CO3 (13.06 g, 94.5 mmol), 1-tert-butoxycarbonylamino-3-bromopropane (22.5 g, 94.5 mmol), and freshly ground potassium iodide (1.5 g). The resulting slurry was placed under a nitrogen atmosphere and stirred for 2.5 days. The slurry was diluted with water (250 mL), washed with 1 N NaOH (2×250 mL), water (250 mL), and brine (250 mL), then dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified on a preparative HPLC chromatograph using two silica columns and a hexanes through 1:1 hexanes:EtOAc gradient to provide methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (19.93 g, 93.3%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](OC)=[O:32])=[CH:25][CH:24]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl.[NH2:43][C:44]1[NH:45][CH2:46][CH2:47][CH2:48][N:49]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31](=[O:32])[NH:43][C:44]2[NH:49][CH2:48][CH2:47][CH2:46][N:45]=2)=[CH:27][CH:28]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
438 mg of tert-butyl (2S)-2-(benzyloxycarbonylamino)-3-(4-(methoxycarbonylmethyloxy)benzoylamino)propionate, 606 mg of potassium tert-butoxide and 732 mg of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride were dissolved in 10 ml of absolute dimethylformamide, and the solution was stirred at room temperature for 14 h and then concentrated to dryness in vacuo.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][S:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:23][S:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CSc1ccccc1CN
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: CSc1ccccc1CNC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2-methylthiobenzylamine (77 mg, 0.5 mmol). The title product was obtained as an off-white solid (34.2 mg, 82% yield). 1HNMR (500 MHz, CDCl3) δ: 12.37 (1H, s), 7.92 (1H, br s), 7.55–7.44 (1H, m), 7.33–7.25 (2H, m), 7.17–7.14 (1H, m), 7.04 (2H, dd, J=8.24, 7.32 Hz), 4.67 (2H, d, J=6.10 Hz), 3.40 (3H, s), 2.44 (3H, s). HRMS (ESI) calcd for C20H16F2N3O3S (M−H): 416.0880; found: 416.0879.
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]([CH3:19])[O:17][CH3:18])=[O:15])=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Cl>CN(C)C=O.O.C(O)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]([CH3:19])[O:17][CH3:18])=[O:15])=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)Nc1ccc(O)cc1
Reactant: COc1ccccc1CCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1ccccc1COc1ccc(NC(=O)N(C)OC)cc1
Temperature: 25 °C

Procedure:
To an ethanolic solution of sodium ethoxide prepared from ethanol (200 ml) and sodium (2.5 g), N-(4-hydroxyphenyl)-N'-methyl-N'-methoxyurea (20 g) is added, and a solution of 2-methoxybenzyl chloride (17 g) in N,N-dimethylformamide (50 ml) is added dropwise thereto. The reaction mixture is gradually heated, kept under reflux for 3 hours and cooled to room temperature. The reaction mixture is poured onto cold water (1 liter). The precipitated crystals are collected by filtration, washed with water, dried and recrystallized from ethanol to give N-[4-(2-methoxybenzyloxy)-phenyl]-N'-methyl-N'-methoxyurea (Compound No. 23) (12 g) as white scales. M.P., 98° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:19]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[N:19]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1nc(-c2cccs2)no1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1csc(-c2noc(COc3ccc(CCCn4ccnc4)cc3)n2)c1
Yield: 41 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 5-chloromethyl-3-(2-thienyl)-1,2,4-oxadiazole to obtain 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-3-(2-thienyl)-1,2,4-oxadiazole. The yield was 41%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 118-119° C.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH2:17][CH3:18])[N:8]3[C:7]=2[N:6]=[C:5]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2CC)[N:4]=1)[CH3:2].N1C=CN=C1>CO>[CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH2:17][CH3:18])[N:8]3[C:7]=2[N:6]=[C:5]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:4]=1)[CH3:2]
Reactant: CCc1nc(-n2ccnc2CC)nc2c1[nH]c(=O)c1cnc(CC)n12
Agent: c1c[nH]cn1
Solvent: CO
Product: CCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(CC)n12

Procedure:
The compound of Example 6 (5 g, 15 mmol) is heated with 50 g of imidazole at 200° C. under N2 for 16 h. The reaction mixture is cooled to ~100° C., and 150 mL methanol is added. The solids are filtered and washed with methanol to provide the title compound.