Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH2:26]>CO>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH:26][CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: CN
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccc(F)cc1F
Solvent: CO
Product: CNC/C=C/CN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.52 g, 1.2 mmol) was treated with 8N methylamine in methanol to give (2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-en-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.27 g, 54%). MS (ES) m/z 365.9 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7](C(OCC)=O)[C:6]1=[O:21].Cl>O1CCOCC1>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@:5]1([CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]1=[O:21]
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A solution of Example 49C (2.65 g, 8.02 mmol) in 1,4-dioxane (25 mL) was treated with aqueous 1 N hydrochloric acid solution (25 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and dried to give 1.62 g (61%) of the title compound. 1H NMR (300 MHz, CDCl3): δ ppm 0.43 m, 0.5 H) 0.83 m, 10 H) 1.06 (m, 0.5 H) 1.51 (s, 1.5 H) 1.56 (s, 1.5 H) 1.83 m, 1 H) 2.02 m, 0.5 H) 2.26 m, 0.5 H) 3.74 (s, 1 H) 6.09 (s, 0.5 H) 7.51 m, 3 H) 8.10 (td, J=7.81, 1.29 Hz, 1 H); MS (ESI−) m/z 257 (M−H)−.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1.C(N(CC)CC)C.[I-].[Na+]>C(O)C>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2o1
Yield: 23 %

Procedure:
To a 100 ml round-bottomed flask equipped with magnetic stirrer, condenser, and nitrogen inlet were added 0.618 g (2.10 mmol) of N-(1-naphthyl)piperazine, 0.472 g (1.95 mmol) of 6-(2-bromoethyl)benzoxazolone, 0.411 ml (2.92 mmol) of triethylamine, 50 ml ethanol, and a catalytic amount of sodium iodide. The reaction was refluxed for 3 days, cooled, and evaporated to a brown gum. The gum was partitioned between 50 ml water and 75 ml methylene chloride, the pH adjusted with aqueous 1N NaOH solution, and a little methanol added to facilitate phase separation. The methylene chloride layer was dried over sodium sulfate and evaporated, then chromatographed on silica gel. Fractions containing the product were combined and evaporated, the residue taken up in ethyl acetate, treated with hydrochloride gas, and the resulting hydrochloride salt of the product filtered off to give the white solid title compound, m.p. 282°-285° C., 213 mg (23% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[N:46][CH:45]=[C:44]([S:48]([N:51]6[CH2:52][CH2:53][O:54][CH2:55][CH2:56]6)(=[O:50])=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=S(=O)(c1cncc(Br)c1)N1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cncc(S(=O)(=O)N4CCOCC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-(5-bromo-pyridine-3-sulfonyl)-morpholine (prepared from 5-bromo-pyridine-3-sulfonyl chloride and morpholine, 60 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-07, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[5-(morpholine-4-sulfonyl)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-248) as an ivory powder (65 mg, 67%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[N:10][O:11][CH3:12])[CH2:6][C:7](=[O:9])[CH3:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH:22]([CH3:24])[CH3:23].Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5](=[N:10][O:11][CH3:12])[CH:6]([C:7](=[O:9])[CH3:8])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CC(C)CI
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)C(CC(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a solution of 2-methoxyimino-4-oxo-pentanoic acid ethyl ester (2.62 g, 14 mmol) in DMF (30 mL) is added potassium carbonate (2.5 g, 18.2 mmol) followed by 1-iodo-2-methyl-propane (1.62 mL, 14 mmol) and the mixture is stirred at ambient temperature overnight. Additional 1-iodo-2-methyl-propane (0.8 mL, 7 mmol) is added and the mixture is stirred at 60° C. for 1 hour. The reaction mixture is diluted with EtOAc and is adjusted to pH 3 with 1N HCl. The organic layer is washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (0 to 20% EtOAc in hexanes) to give the title compound as a colorless oil (1 g, 29%). 1H NMR (400 MHz, CDCl3) δ 4.33 (q, 2H), 4.06 (s, 3H), 4.03 (dd, 1H), 2.07 (s, 3H), 1.88 (m, 1H), 1.58 (m, 1H), 1.43 (m, 1H), 1.37 (t, 3H), 0.89 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:25])=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]=[C:16]([CH3:25])[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: CC(=Cc1ccc(F)cc1)CBr
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=Cc1ccc(F)cc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl)-4-fluorobenzene, the title compound was synthesized according to Reference Example 17a. Yield: 52%. Melting point: 164-165° C. (Ethyl acetate-hexane).
Reaction SMILES: CC(C)([O-])C.[K+].C([NH:10][C:11]1[C:12]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[C:13]([C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])(=O)C>CN1CCCC1=O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:11]2[NH:10][C:25]([CH2:26][CH2:27][CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)=[CH:24][C:12]=2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])([O-:23])=[O:22]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(NC(C)=O)c1C#CCCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCOC3CCCCO3)cc12
Temperature: 70 °C
Yield: 84.5 %

Procedure:
Potassium tert-butoxide (0.230 g) was added to a solution of methyl 3-acetylamino-6-nitro-2-[5-(tetrahydropyran-2-yloxy)-pent-1-ynyl]benzoate (Intermediate 23, 0.70 g) in anhydrous N-methyl-2-pyrrolidone (18 mL) and the reaction mixture was heated at 70° C. for 1 hour. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 5-nitro-2-[3-(tetrahydropyran-2-yloxy)-propyl]-1H-indole-4-carboxylate (0.530 g) as a dark orange gum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:10][C:9]1=2
Reactant: COC(=O)CCl
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc2c(c1)CCCC2=O

Procedure:
1 mol of 6-hydroxy-1-tetralone, 1.2 mols of methyl chloroacetate, 2 mols of potassium carbonate and 0.1 mol of potassium iodide are boiled under reflux in 2 l of butanone for 6 hours. The mixture is filtered, the residue is rinsed with acetone and the filtrate is evaporated. The residue is taken up in methylene chloride, and the mixture is washed 3 times with 0.5N NaOH solution, dried over sodium sulphate and evaporated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([OH:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 0.25 g (0.82 mmol) (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 mL N,N-dimethylformamide, 40 mg (0.90 mmol) sodium hydride (55–65% dispersion in oil) was added. After 30 min., 0.10 mL (0.23 g, 1.64 mmol) methyl iodide was added. After 1 h the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water, then brine and were dried over magnesium sulfate. After filtration and evaporation of the solvent the product was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:5) as eluant.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][N:5]2[CH:8]=[CH:9][NH:10][C:4]=12)#[N:2].S(=O)(=O)(O)[OH:12].[OH-].[NH4+]>>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[CH:8]=[CH:9][NH:10][C:4]=12)(=[O:12])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2cc[nH]c12
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnn2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Cyano-1H-imidazo[1,2-b]pyrazole (3 g) was added to conc. sulfuric acid under ice-cooling. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was cooled at 0°-5° C. and carefully poured into ice water (30 ml). The aqueous solution was neutralized with conc. ammonium hydroxide solution and stirred for 1 hour under ice-cooling. The precipitate was collected, washed with cold water and dried over phosphorus pentoxide in vacuo to give 7-carbamoyl-1H-imidazo[1,2-b]pyrazole (3.45 g).
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]2[CH2:28][C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=4)[N:20]=[CH:19][C:18]=3[O:17][CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[O:35][CH2:34]1>>[CH3:30][O:29][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[N:20]=[CH:19][C:18]1[O:17][CH2:16][CH:15]([CH2:14][C@H:11]3[CH2:10][CH2:9][C@H:8]([NH:7][C:6]([C:40]4[CH:41]=[CH:42][C:36]5[O:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:31])[CH2:13][CH2:12]3)[CH2:28][C:27]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1)CC(C[C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CO4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilized powder following Scheme 4 and in analogy to Example 1 using [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid as starting material.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Cl>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=3[Cl:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1ccc(CCl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1ccc(F)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl) phenyl]-4-methyl-1,3-oxazolidin-2-one (1.0 g, 3.19 mmol)/THF (40 mL) at 0° C., was added NaH (153 mg, 60 w/w % in mineral oil, 3.83 mmol, 1.2 eq.) in one portion. The resulting foaming mixture was stirred in an ice bath for 30 min, followed by addition of 2-chloro-4-fluorobenzyl chloride (572 mg, 3.19 mmol). The resulting mixture was stirred at 0° C. for 30 min then warmed to ambient overnight. The reaction failed to proceed at room temperature and it was warmed in a 60° C. oil bath for 20 h. An aliquot indicated that the reaction was over. It was quenched with aq. NH4Cl (50 mL). Volatiles were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to a yellow oil. The oil was purified by SiO2 (Biotage 40+M cartridge, eluted by EtOAc/hexanes, gradient; 5% to 40%). The titled compound was obtained as a colorless glassy material. LC-MS: 456.12 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.77 (s, 2H), 7.46 (dd, J=8.7, 6.0 Hz, 1H), 7.17 (dd, J=8.4, 2.5 Hz, 1H), 7.03 (m, 1H), 5.68 (d, J=8.2 Hz, 1H), 4.83 (d, J=15.6, 1H), 4.36 (d, J=15.3 Hz, 1H), 4.06 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:22]1=[O:37])[CH3:20].[H-].[Na+]>>[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:2]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]4[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=4[N:3]=3)=[CH:34][CH:35]=2)[C:22]1=[O:37])[CH3:20]
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 200 °C
Yield: 94.5 %

Procedure:
2-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (1.861 g) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.4 g) and sodium hydride (0.263 g) in DMF(dry) (10 mL) at room temperature. The mixture was heated at 200° C. for 1 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.60 g) as a colorless solid. A mixture of 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (194 mg) and 2 M HCl in EtOH (6.0 mL) was stirred at 70° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was recrystallized from EtOH-ether to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (154 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][C:23]([NH:25][C@H:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=S.[NH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][C:23]([NH:25][C@H:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[NH:34]
Reactant: N
Reactant: COc1cc2c(NC(=S)N[C@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(NC(=N)N[C@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 29, 1 [6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]-3-[(R)-(+)-α-methylbenzyl]thiourea was reacted with ammonia to give the title compound; NMR Spectrum: (CDCl3)1.38-1.42 (m, 2H), 1.61 (d, 3H), 1.86-2.01 (q, 5H), 2.29 (s, 3H), 2.89 (d, 2H), 3.95 (m, 3H), 4.0 (d, 2H), 4.7 (q, 1H), 6.5 (br s, 1H), 7.12 (s, 1H), 7.29-7.31 (m, 5H), 7.79 (s, 1H), 8.53 (s, 1H); Mass spectrum: M+H+ 449.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:3]=1[NH:16][C:17]([C:19]1[NH:20][CH:21]=[C:22]([C:24]#[N:25])[N:23]=1)=[O:18].[O:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:4]2[C:3]([NH:16][C:17]([C:19]3[NH:20][CH:21]=[C:22]([C:24]#[N:25])[N:23]=3)=[O:18])=[CH:2][CH:7]=[C:6]([C:29]3([OH:32])[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[N:5]=2)=[CH:9][CH2:10]1
Reactant: O=C1CCOCC1
Reactant: CC1(C)CC=C(c2nccc(Br)c2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2nc(C3(O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1 step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridine-3-yl]-amide (as prepared in the Example 32 steps (d)) and tetrahydropyran-4-one. Mass spectrum (ESI, m/z): Calcd. for C25H27N5O3, 422.2 (M+H). found 422.2.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:28][CH:27]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylic acid (Intermediate 21) and 4-(methylsulfonyl)aniline (Enamine), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([O:12][C@H:13]([CH2:39][O:40][C:41](=[O:51])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:14][S:15][CH2:16][C@@H:17]([C:36]([OH:38])=O)[NH:18]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][P:64](=[O:71])([O:68]CC)[O:65]CC>>[NH2:18][C@@H:17]([CH2:16][S:15][CH2:14][C@H:13]([O:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:39][O:40][C:41](=[O:51])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:36](=[O:38])[NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][P:64](=[O:65])([OH:71])[OH:68]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCC
Product: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)CCCCCCCCC

Procedure:
The title product was prepared from (5R,9R)-9-(decanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azahenicosane-5-carboxylic acid (1 eq) and diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4) by following the procedure described for example 20, step 6-8. 1H NMR (CDCl3): δ 8.67 (br s, 1H), 5.07-5.16 (m, 1H), 3.29 (dd, 1H), 4.08 (dd, 1H), 3.40-3.73 (m, 13H), 3.26-3.38 (m, 2H), 3.02 (dd, 1H), 2.87-2.97 (m, 1H), 2.78 (dd, 1H), 2.68 (dd, 1H), 2.18-2.29 (m, 4H), 1.75-1.89 (m, 2H), 1.46-1.59 (m, 4H), 1.10-1.31 (m, 24H), 0.81 (t, 6H). LRMS [M+H]=743.5.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCO>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2[N+](=O)[O-])c1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2N)c1
Reaction time: 2.5 h

Procedure:
2-(3-tert-Butyldimethylsilyloxyphenyl)nitrobenzene, as described above in Step C, (11.94 g, 36.24 mmol) was dissolved in EtOH (250 mL) and EtOAc (250 mL), degassed with argon and Pd/C (1.19 g, 10 wt %) was added. The vessel Was subjected to H2 (1 atm) while vigorously stirring for 2.5 hour. The reaction was filtered through a celite pad and concentrated in vacuo, to yield the above-titled compound.