Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1/[CH:34]=[CH:35]/[O:36][CH2:37][CH3:38].[CH3:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:41]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[CH2:37]([O:36]/[CH:35]=[CH:34]/[C:3]1[C:2]([C:41]2[N:42]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:43]3[C:48]([C:40]=2[CH3:39])=[CH:47][CH:46]=[CH:45][CH:44]=3)=[N:7][C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23](=[O:24])[NH:25][CH3:26])[C:12]=3[CH:27]=2)=[CH:5][CH:4]=1)[CH3:38]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)n(C(=O)OC(C)(C)C)c2ccccc12
Reactant: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1c(C)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a mixture of (E)-5-(6-chloro-5-(2-ethoxyvinyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.269 mmol), tert-butyl 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (144 mg, 0.403 mmol), cesium carbonate (175 mg, 0.538 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (17.5 mg, 0.027 mmol) was added 1,4-dioxane (2.44 mL) and H2O (0.244 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 90° C. for 10 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/Hexanes as eluent. MS (M+H): 753.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@@:7]2([CH3:27])[N:11]3[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:10]3[N:9]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.Cl.[C:31]([O:35][C:36](=[O:40])[C@@H:37]([NH2:39])[CH3:38])([CH3:34])([CH3:33])[CH3:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[C:31]([O:35][C:36](=[O:40])[C@@H:37]([NH:39][C:15]([C:12]1[N:11]2[C@@:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([Br:1])=[CH:3][CH:4]=3)([CH3:27])[C:8](=[O:26])[N:9]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)[C:10]2=[N:14][CH:13]=1)=[O:17])[CH3:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 80.3 %

Procedure:
To a solution of (R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (2.5 g, 5.0 mmol) in DMF (5 mL) was added (S)-2-amino-propionic acid tert-butyl ester hydrochloride (0.92 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol), EDC (0.97 g, 5.0 mmol) and DMAP (0.061 g, 0.50 mmol). The reaction mixture was heated at 80° C. for 12 h. The mixture was allowed to cool to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated in vacuo to give 2.5 g of (S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid tert-butyl ester as a yellow solid, m/z 623.5 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3oc2=O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=c1oc2cc(O)ccc2cc1-c1ccc(O)cc1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
7-Methoxy-3-(4-methoxyphenyl)-chromen-2-one (21.8 g) was mixed with pyridine hydrochloride (80 g) and stirred for 1 hour at a temperature of 190° C. to 200° C. Water was added to the reaction mixture and the resulting precipitates were collected by filtration and dried under reduced pressure to give 7-hydroxy-3-(4-hydroxyphenyl)-chromen-2-one (19.6 g, Yield 100%). Diisopropylethylamine (35 ml)in dimethylformamide (70 ml) and methoxymethyl chloride (10.4 ml) were added to a solution of 7-hydroxy-3-(4-hydroxyphenyl)-chromen-2-one thus prepared (8.74 g) followed by stirring for 2 hours at 80° C. After cooling, water was added to the reaction mixture and the resulting precipitates were collected by filtration and dried under reduced pressure to give 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)chromen-2-one (8.67 g, Yield 74%).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20].Cl>CCOCC.CCCCCC>[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]([NH2:3])=[NH:20]
Reactant: COc1cccc(C#N)c1OC
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(C(=N)N)c1OC
Reaction time: 0.17 h

Procedure:
To a solution of 20 g 1,1,1,3,3,3-hexamethyldisilazane in 150 mL dry ether was added 5 mL 2.4 M n-butyllithium in hexane. After 10 min at room temperature,16.3 g 2,3-dimethoxybenzonitrile was added in one portion and the mixture was kept at room temperature for 16 h. The reaction mixture was then poured onto excess 3N HCl. The aqueous layer was separated, basified with 50% NaOH and the product was extracted three times with 10% methanol in methylene chloride. The combined organic extracts were dried over potassium carbonate and the solvents removed in vacuo to afford 2,3-dimethoxybenzamidine as a glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3ccc(C)cc3nc2OC)CC1
Yield: 90 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.09-3.18 (m, 4H), 3.77-3.82 (m, 4H), 3.88 (s, 3H), 4.13 (s, 3H), 6.87-7.80 (m, 8H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=2)[CH3:18])[C:13]([CH3:33])=[N:12]1.[OH-].[Na+].Cl>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21](=[O:32])[C:22]2[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=2)[CH3:18])[C:13]([CH3:33])=[N:12]1
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc4ccccc4n3)N=C2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=NN(c2ccc3ccccc3n2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)O)cc1
Yield: 33.6 %

Procedure:
1.5 mL of a methanol solution of 14.9 mg (0.034 mmol) of the 4-methoxycarbonylbenzoic N′-(1-(1-(quinolin-2-yl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide synthesized in 1) was stirred with 168 μL (0.168 mmol) of 1M aqueous sodium hydroxide at 50° C. for 12 hours. After the stirring, 168 μL (0.168 mmol) of 1M hydrochloric acid was added, and the precipitated solid was collected by filtration to obtain 4.9 mg of the desired product as a dark yellow solid (yield 34%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[C:7]([C:12]3(O)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[OH-].[Na+]>Cl>[CH3:2][N:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH2:13][NH:14][CH2:15][CH2:16][CH:17]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: Cn1ccc2c(C3(O)CCCNC3)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc2c(C3=CCCNC3)cccc21
Yield: 62.8 %

Procedure:
A solution of 12 g of the product of Example 19 in 360 ml of 1 N hydrochloric acid was refluxed for 4 hours and was cooled in an ice bath while adding sodium hydroxide solution until the pH was alkaline. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium chloride solution, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 6 g of 1-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NCCC2=O
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CCNc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A solution of 1.1 g (6.2 mmol) of 7-methoxy-1,2,3,4-tetrahydro-4-quinolinone (Rec. Trav. Chim., 1963;82:39) in 35 mL of CH2Cl2 was cooled in ice and treated with 5.0 mL of BBr3. After stirring at 0° C. for 0.5 hour, the solution was allowed to stir at room temperature overnight. The solution was poured into ice water and made basic with 50% NaOH. After extracting with Et2O, the pH was brought to 5.5 with dilute HCl, and the solution extracted twice with EtOAc. The EtOAc was washed with saturated NaCl and dried over MgSO4. Removal of the solvent under reduced pressure gave 0.5 g (49.5% yield) of the product as an orange solid. The structure was confirmed by NMR and mass spectroscopy. MS m/z 164 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 51.3 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), the above-mentioned 3-ethoxybenzyl chloride (636 mg) and potassium carbonate (515 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 60° C. for 14 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to remove the solvent, and the residue was subjected to purification using silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (308 mg) as a yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]P(OC)(OC)=O)=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]([O:32][C:33]([N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:45]([CH:51]=O)[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:43]=2)[C:38]([CH3:54])([CH3:53])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:45]([CH:51]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:17])=[CH:9][CH:8]=3)[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:43]=2)[C:38]([CH3:53])([CH3:54])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCCCCC(C=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Reactant: COC(=O)c1ccc(CP(=O)(OC)OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: -20 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
A solution of 4-(dimethoxyphosphorylmethyl)-benzoic acid methyl ester (0.94 g, 3.6 mmole) in 10 mL of THF at −20° C., was treated with 3.7 mL of 1M lithium bis(trimethylsilyl)amide solution in hexanes. After 20 minutes at −20° C. a solution of 7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.91 g, 2.4 mmole) in 5 mL of THF was added. The reaction mixture was stirred at −20° C. for 30 minutes, at room temperature for 6 hours, quenched by the addition of 10 mL of saturated aqueous ammonium chloride solution and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.98 g of 7-{1-[2-(4-methoxycarbonyl-phenyl)-vinyl]-hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+]([O-])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)(=[O:4])=[O:3].[Cl-].[NH4+:17].CO>[Zn].O>[CH3:1][S:2]([C:5]1([NH2:17])[CH:6]=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: COc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC1=CC(N)(S(C)(=O)=O)CC=C1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a mixture of 1-methanesulfonyl-3-methoxy-5-nitro-benzene (1.5 g, 6.48 mmol), zinc dust (4.3 g, 64.87 mmol), and ammonium chloride (5.2 g, 97.31 mmol) were added methanol (20.32 mL) and water (9.9 mL) at room temperature. After addition of water, the reaction was exothermic. The suspension was stirred for 30 min and the reaction mixture was filtered through the Celite. The filter cake was washed with water and methanol. The filtrate was concentrated to remove methanol and the residue was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to isolate 1-methanesulfonyl-5-methoxy-phenylamine (1.0 g, 76%) as a light yellow solid: ES(+)-HRMS m/e calcd for C8H12NO3S (M+H)+ 202.0533, found 202.0532.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([O-])=O.[CH:34]1([NH:37][C:38]([CH:40]2[O:45][CH2:44][CH2:43][NH2+:42][CH2:41]2)=[O:39])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:42]3[CH2:43][CH2:44][O:45][C@@H:40]([C:38]([NH:37][CH:34]4[CH2:35][CH2:36]4)=[O:39])[CH2:41]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(NC1CC1)C1C[NH2+]CCO1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCO[C@@H](C(=O)NC4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 1 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.1 g, 2.7 mmol) was added to a solution of 2-[(cyclopropylamino)carbonyl]morpholin-4-ium trifluoroacetate (0.92 g, 3.2 mmol) (see the following step B for preparation) and DIPEA (1.5 mL, 8.1 mmol) in DCE at 80° C. The reaction mixture was stirred for 1 h and washed with saturated NaHCO3 solution, water and brine. The solvent was concentrated to provide the racemic title compound as white solid. The enantiomers were separated by chiral preparative HPLC to provide the title compounds.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1)[CH:35]=[CH2:36].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:34]([N:37]1[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:41][CH2:42]1)[CH:35]=[CH2:36]
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: C=CCN1CCN(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (300 mg, 1.43 mmol), (prepared as described for the starting material in Example 4), in methylene chloride (15 ml) was added triphenylphosphine (522 mg, 2.0 mmol), 3-(4-allylpiperazin-1-yl)propan-1-ol (288 mg, 1.57 mmol), (DE 2755707), and diisopropyl azodicarboxylate (336 μl, 1.71 mmol) and the mixture stirred at ambient temperature for 2 hours. The crude reaction mixture was loaded directly onto a silica chromatography column and eluted with methylene chloride/methanol (95/5). The volatile solvents were removed under vacuum to give 7-[3-(4-allylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline as an oil which crystallised on standing (480 mg, 89%).
Reaction SMILES: [NH:1]([C:29]([CH3:31])=[O:30])[C@@H:2]([C:10]([NH:12][C@H:13]([C:25]([O:27]C)=[O:26])[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]2)=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O>O1CCOCC1.O>[NH:1]([C:29]([CH3:31])=[O:30])[C@@H:2]([C:10]([NH:12][C@H:13]([C:25]([OH:27])=[O:26])[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]2)=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)[C@@H](Cc1ccccc1)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Yield: 113.5 %

Procedure:
A solution of N-Ac-D-Phe-2-Nal-OMe (1.55 g) in 20 ml of dioxane/water=9/1 (v/v) was treated with sufficient 6N sodium hydroxide to keep the pH at 12 for 1 hours at room temperature. After acidification, the mixture was poured into water and was extracted with dichloromethane. The organic layer was washed with water and was dried on sodium sulfate. The filtrate was evaporated and yielded 1.7 g crude N-Ac-D-Phe-2-Nal-OH.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:29][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(c1ccccc1)C(C(=O)O)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
1-Hydroxy-6-methoxy-1,3-diphenyl-1H-indene-2-carboxylic acid ethyl ester (110 mg, 0.285 mmol) prepared in Example 1 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 24 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 99 mg of the titled compound (yield: 97%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1.OCC1NN=C(C2C=CC(C3N=C4N(CCC5CCOCC5)C(=O)NC4=NC=3)=CC=2)[N:35]=1>S(Cl)(Cl)=O>[NH2:35][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=c1[nH]c2ncc(-c3ccc(-c4n[nH]c(CO)n4)cc3)nc2n1CCC1CCOCC1
Reactant: O=c1[nH]c2ncc(-c3ccc(-c4n[nH]c(CCl)n4)cc3)nc2n1CCC1CCOCC1
Solvent: O=S(Cl)Cl
Product: NCc1nc(-c2ccc(-c3cnc4[nH]c(=O)n(CCC5CCOCC5)c4n3)cc2)n[nH]1
Yield: 81 %

Procedure:
6-(4-(5-(Chloromethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.130 g, 0.31 mmol) in thionyl chloride (2 mL) was stirred in a sealed tube at 80° C. for 1 h. The cooled reaction solvent was removed under reduced pressure. The resulting material was dried under vacuum at 50° C. to give the desired product (0.110 g, 81%) as a white solid. MS (ESI) m/z 440.0[M+1]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[C@H:17]1[CH3:21])([CH3:15])[CH3:14]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1cc(N2CC[C@H](C(C)(C)O)[C@@H]2C)ccc1C#N

Procedure:
Using 4-fluoro-2-methoxybenzonitrile (352 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (470 mg) and lithium carbonate (188 mg), the title compound was obtained as an orange solid (yield: 195 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])=[C:11](I)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])=[C:11]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2ccc(Cl)c(Cl)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(Cl)c(Cl)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [2-(3,4-dichloro-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 105) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 485.3 (MH+, 2Cl).