Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:21]=2)[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41]Br)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:43])[NH:39][CH2:40][CH2:41][N:16]1[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:31]=[CH:32][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:19]=2)[CH2:14][CH2:15]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCNCC3)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: CC(C)(C)OC(=O)NCCN1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 85.9 %

Procedure:
Following the procedure of Example 11(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine 0.35 g (0.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.183 g, 0.82 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): 1.39 (9H, s), 2.28 (6H, m), 3.04 (2H, m), 3.54 (2H, m), 6.65 (1H, brs), 6.98 (2H, d), 7.05 (1H, t), 7.25 (4H, d), 7.88 (4H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C(#N)C>[C:24]([CH2:23][CH2:22][CH2:21][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1)#[N:25]
Reactant: N#CCCCBr
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCN(c2ccccc2F)CC1
Yield: 98 %

Procedure:
2-Fluorophenyl piperazine (6.5 g) are suspended in acetonitrile (50 ml), anhydrous K2CO3 (1.5 eq) and 4-bromobutyronitrile (1.05 eq) in acetonitrile (25 mL) are added dropwise. The mixture is heated at reflux for 10 h and then filtered, the filtrate is concentrated in vacuo. The residue is taken up in AcOEt and washed three times with water. The organic layer is extracted with hydrochloric acid (1M) and the aqueous acid layer is washed with AcOEt and neutralized with aqueous ammonia (28% in H2O) to pH 11. The extraction is carried out with AcOEt and the organic layer is washed twice with water and dried over Na2SO4. The mixture is concentrated to give the title compound (8.35 g, 98%). 1H NMR (200 MHz, CDCl3) δ 1.80-1.90 (m, 2 H), 2.42-2.49 (m, 2H), 2.52-2.56 (m, 2H), 2.59-2.64 (m, 4H), 3.07-3.13 (m, 4H), 6.91-7.07 (m, 4H). RMN 13C (50 MHz, CDCl3): δ 14.8, 22.6, 50.4, 53.0, 56.2 115.8, 116.2 118.8, 119.7, 122.3, 122.5, 124.3, 124.4, 153.1, 158.0.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:33][CH2:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]1)=[O:36].CCOC(OC(OCC)=O)=O>CN(C=O)C.O>[OH2:7].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][N:13]([C:43]([CH:40]3[CH2:41][CH2:42][N:37]([C:35](=[O:36])[CH2:34][OH:33])[CH2:38][CH2:39]3)=[O:44])[CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(O)C1CCN(C(=O)CO)CC1
Reactant: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)CO)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of the compound obtained in step 3 (200 mg), triethylamine (313 μL) and 1-(hydroxyacetyl)piperidine-4-carboxylic acid (101 mg) in DMF (4.5 mL) was added DEPC (87 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 40→95% ethyl acetate/hexane) to give the title compound (135 mg, 49%) as a white crystal powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:34]1[CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (19 mmol) of 2,4-difluorobenzoic acid and 4 mL of DIEA (1.2 equiv.) in 40 mL of dry DCM is added 3.08 g (1.2 equiv) of HOBt and 4.2 g (22.55 mmol) of t-butyl piperazine-1-carboxylate, and the mixture was stirred at RT for 30 min. 4.4 g (11 equiv.) of EDCl are added and the reaction mixture is stirred overnight at RT. Water is added and the resulting mixture is extracted with DCM. The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain t-butyl 4-(2,4-difluorobenzoyi)piperazine-1-carboxylate as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 3.30 (m, 2H), 3.41 (m, 2H), 3.53 (m, 2H), 3.76 (m, 2H), 6.86 (dt, 1H, J=8.8 Hz and 0.8 Hz), 6.97 (dt, 1H, J=8.8 Hz and 0.8 Hz), 7.41 (dd, 1H, J=14.4 Hz and 7.2 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].CCN(CC)CC.[CH3:22][NH:23][CH2:24][CH:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27][CH2:26]1>O1CCOCC1>[CH2:1]([O:4][C:5]([C:7]1[C:8]([N:23]([CH3:22])[CH2:24][CH:25]2[CH2:32][CH2:31][C:28]3([CH2:29][CH2:30]3)[CH2:27][CH2:26]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CNCC1CCC2(CC1)CC2
Reactant: C=CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1cnc(Cl)nc1N(C)CC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of the 2,4-dichloropyrimidine-5-carboxylic acid allyl ester (1.6 mmol) in dioxane (6 mL) is added Et3N (2.4 mmol) at room temperature. A solution of methyl-spiro[2.5]oct-6-ylmethylamine (1.6 mmol) in dioxane (2.0 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 12 h and the reaction is quenched by the addition of water. The mixture is extracted with CH2Cl2. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound (370 mg); 1H NMR (CDCl3) δ 0.15-0.19 (m, 2H), 0.25-0.29 (m, 2H), 0.87-0.91 (m, 2H), 1.08-1.20 (m, 2H), 1.60-1.85 (m, 5H), 2.95 (s, 3H), 3.59 (d, 2H), 4.77-4.78 (m, 2H), 5.29-6.08 (m, 1H), 8.48 (s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6]C(=O)C2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH:12][OH:13].[C:14]([O:17]CC)(=[O:16])[CH3:15]>>[CH:8]1[CH:9]=[C:10]([O:12][OH:13])[C:2]([C:1]([OH:6])=[O:11])=[C:15]([C:14]([OH:17])=[O:16])[CH:7]=1
Reactant: OO
Reactant: CCOC(C)=O
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1cccc(OO)c1C(=O)O
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
25 grams of phthalic anhydride were dissolved in 150 ml of ethyl acetate and cooled to 10° C. Then there were added 3 grams of Lewatit MP 62. Subsequently, within 15 minutes, there were dropped in at the same temperature with stirring 11.5 grams of 50 wt. % hydrogen peroxide. Stirring was containued for 1 hour, whereby the temperature of the mixture increased to about 20° C. Then there was separated off the ion exchanger and there were obtained from the solution 25.4 grams of monoperoxyphthalic acid having an AO content of 7.0%.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=1.[CH3:24]C(C)([O-])C.[K+].CI>CN(C=O)C.CCOC(C)=O>[CH3:24][N:12]1[C:13]2[CH2:1][N:2]([C:14]3[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=3)[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCc3c(n(C)c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 76.5 %

Procedure:
To a stirred solution of Example 8 (200 mg, mmol) in DMF (5 mL) was added potassium t-butoxide (145 mg) at 0° C. After stirring the suspension for 10-15 min at 0° C., methyl iodide (0.11 g, mmol) was added. The mixture was stirred at 0° C. for 30 min. and then stirred at room temperature for 3 hours. After completion, the reaction mixture was diluted with EtOAc. The organic layer was separated, washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain methyl 2-(9-methyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylate (160 mg, 76.5% yield). 1HNMR (DMSO-d6) ppm: 2.8 (t, 2H, CH2); 3.65 (s, 3H, N—CH3); 3.8 (s, 3H, OCH3); 4.2 (t, 2H, CH2); 5.15 (s, 2H, CH2); 7.0-7.2 (m, 2H); 7.4 (d, 2H); 8.8 (s, 2H); m/e=323 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18](=[CH:28][OH:29])[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 42 %

Procedure:
6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-1,3-dihydro-indol-2-one (0.100 g, 0.278 mmol) and ethyl formate (0.066 mL, 0.834 mmol) were dissolved in anhydrous ethanol (0.600 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.519 mL, 1.39 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered yielding 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-3-hydroxymethylene-1,3-dihydro-indol-2-one as an orange solid in 42% yield (0.045 g, 0.117 mmol). (prepared below, 0.021 g, 0.056 mmol)
Reaction SMILES: [F:1][C:2]1[C:3]([I:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14]CC)=[O:13])[O:7][CH2:6][CH2:5]2.O[Li].O>CO.C1COCC1.O>[F:1][C:2]1[C:3]([I:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[O:7][CH2:6][CH2:5]2
Reactant: CCOC(=O)C1OCCc2c1ccc(F)c2I
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1OCCc2c1ccc(F)c2I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-fluoro-5-iodo-3,4-dihydro-1H-isochromene-1-carboxylate (1.6 g, 4.5 mmol) in 25 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (700 mg, 18.3 mmol), and the mixture was stirred at ambient temperature for 30 min. The solvents were removed under vacuum, and the residue was added 50 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 6-fluoro-5-iodo-3,4-dihydro-1H-isochromene-1-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16](Br)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[C:37]4=[N:38][CH:39]=[CH:40][CH:41]=[C:36]4[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:34]3=[O:50])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>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.O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[C:37]5=[N:38][CH:39]=[CH:40][CH:41]=[C:36]5[N:35]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[C:34]4=[O:50])=[CH:29][CH:28]=3)[C:11]=2[N:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-n3c(=O)n(COCC[Si](C)(C)C)c4cccnc43)cc2)OC1(C)C
Reactant: Cc1nc2c(Br)cccc2n1Cc1ccccc1
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: O
Solvent: C1CCOC1
Product: Cc1nc2c(-c3ccc(-n4c(=O)n(COCC[Si](C)(C)C)c5cccnc54)cc3)cccc2n1Cc1ccccc1
Temperature: 100 °C
Yield: 53.5 %

Procedure:
Benzyl chloride (1.527 mL) was added to a solution of 4-bromo-2-methyl-1H-benzimidazole (1.40 g) and sodium hydride (0.531 g) in DMF (10 ml) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (1.88 g) as tan oil. The mixture of 1-benzyl-4-bromo-2-methyl-1H-benzo[d]imidazole (496 mg), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (700 mg), Pd(Ph3P)4 (87 mg), sodium carbonate (476 mg) and THF (18 mL)-water (0.90 mL) was heated at 100° C. for 1 h under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 3-[4-(1-benzyl-2-methyl-1H-benzimidazol-4-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (450 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:7][O:6][C:5]([CH2:14][S:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]2[C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:29][CH:28]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.O.C(N(CC)CC)C>CO>[CH3:1][C:2]1([CH3:40])[CH2:3][O:4][C:5]([CH2:14][S:15][C@H:16]2[C:19](=[O:20])[N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]2[C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:38][CH:39]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:6][CH2:7]1
Reactant: CCOC(=O)COc1ccc([C@@H]2[C@@H](SCC3(c4ccccc4)OCC(C)(C)CO3)C(=O)N2c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)COC(CS[C@H]2C(=O)N(c3ccccc3)[C@@H]2c2ccc(OCC(=O)O)cc2)(c2ccccc2)OC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl [4-((2R,3R)-3-{[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}-4-oxo-1-phenylazetidin-2-yl)phenoxy]acetate (0.86 g, 1.53 mmol) in MeOH (25 ml) was added water (2.5 ml) and triethylamine (1.55 g). The reaction was stirred for 48 h at 50° C. The solvent was evaporated and the residue was purified by preparative HPLC using a gradient of 20-70% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions gave the title compound as a colourless solid. 1H NMR [(CD3)2SO), 400 MHz]□0.50 (s, 3H), 1.15 (s, 3H), 2.93 (d, 1H), 2.96 (d, 1H), 3.21-3.37 (m, 4H), 4.13 (d, 1H), 4.28 (s, 2H), 4.97 (d, 1H), 6.83-7.41 (m, 14H).
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[C:9]([O:13][C:14]([N:16]1[C@H:21]([C:22](=[O:33])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[CH2:20][C@:19]2([CH2:34]OS(C)(=O)=O)[C@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].O>C1COCC1>[C:9]([O:13][C:14]([N:16]1[C@H:21]([C:22](=[O:33])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[CH2:20][C@:19]2([CH3:34])[C@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(COS(C)(=O)=O)C[C@@H]12
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(C)C[C@@H]12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Lithium triethylborohydride (1N in THF, 2.06 mL, 2.06 mmol) was added at 0° C. to a solution of (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-methanesulfonyloxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (385 mg, 0.67 mmol) in THF (6.8 mL) under argon atmosphere. The solution was stirred 10 min at 0° C., then poured into cold water and extracted with EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 75:25). TLC, Rf (c-hexane/EtOAc 1:1)=0.55; MS (UPLC/MS): 383.3/385.3 [M+H]+, 427.5/429.4 [M+HCOO]−; tR (HPLC conditions f): 2.24 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:17][C:18](=O)[CH2:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH2:21][C:22]([OH:24])=[O:23])([O-])=O.Cl.[C:34]([O-])(O)=O.[Na+].C(OCC)(=O)C>CO.Cl.[Fe]>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:20]([CH2:19][C:18]2[NH:1][C:4]3[CH:9]=[C:8]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:7]=[CH:6][C:5]=3[N:17]=2)[CH2:21][C:22]([O:24][CH3:34])=[O:23])=[CH:26][CH:27]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC(Cc1nc2ccc(Oc3ccccc3)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-Nitro-4-phenoxyphenyl)-3-(4-chlorophenyl)glutaramic acid (0.72 g) is dissolved in methanol (8 ml). Iron powder (0.88 g) is added and the suspension is heated to reflux. Conc. HCl (10 drops) was added carefully and refluxing was continued for 1 h. Then further conc. HCl (4 ml) was added and the greenish-yellow solution was stirred at reflux for additional 20 h. After cooling to rt the solution was poured into a mixture of sat. NaHCO3 solution (60 ml) and ethyl acetate (50 ml). The inorganic precipitates were removed by suction filtration and subsequently washed with ethyl acetate. From the filtrate the organic layer was separated and the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried (sodium sulfate), concentrated and dried in vacuo. The residue (0.61 g of brownish oil) was purified by flash chromatography (dichloromethane/2% methanol/1% triethyl amine) on silica gel to give methyl 3-(4-chlorophenyl)-4-(5-phenoxy-2-benzimidazolyl)butanoate (0.46 g) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[C:5]=2[C:14]=1[CH3:21])=[O:29]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1OC
Yield: 90 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 3,4-dimethoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 90%. Melting point: 169-171° C. (Ethyl acetate-hexane).
Reaction SMILES: [O:1]=[C:2]([CH2:13][CH3:14])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)[O:21][C:20](=O)[CH:19]=[C:18]([CH3:23])O1.C(C1(C)OC(=O)C=C(C)O1)C>>[CH2:13]([C:2]1[O:1][C:18]([CH3:23])=[CH:19][C:20](=[O:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:14]
Reactant: CCC(=O)CC(=O)Nc1ccccc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: CCC1(C)OC(=O)C=C(C)O1
Product: CCc1oc(C)cc(=O)c1C(=O)Nc1ccccc1
Yield: 49 %

Procedure:
The title compound was prepared from 3-oxo-N-phenylvaleramide (m.p. 84.0°-85.5° C.) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one, instead of 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one in Example 15, as the raw materials in a similar way to the method described in Example 15. (Yield: 49%) m.p.: 154.5°-156° C.
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:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][C@H:54]([CH3:56])[O:53][C@H:52]([CH3:57])[CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:58]>>[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]=[CH:46][C:45]([C:48]([N:50]6[CH2:55][C@H:54]([CH3:56])[O:53][C@H:52]([CH3:57])[CH2:51]6)=[O:49])=[CH:44][C:43]=5[CH3:58])[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: Cc1cc(C(=O)N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4C[C@@H](C)O[C@@H](C)C4)cc3C)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 (50 mg) and (4-bromo-3-methyl-phenyl)-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone (44 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-246) as a pale yellow powder (22 mg, 45%).
Reaction SMILES: [C:1]1([C:11]([O:13]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>C(O)C>[C:1]1([C:11]([NH:16][NH2:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc2ccccc12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc2ccccc12

Procedure:
The synthesis method of Example 2-(1) was applied. The compound (43.1 g) obtained in (1) above, hydrazine monohydrate (200 ml) and ethanol (80 ml) were used as reagents. After the reaction, a white solid was quantitatively obtained.