Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:7]3[C:2]([F:1])=[CH:3][C:4]([N+:19]([O-:21])=[O:20])=[C:5]([NH:9][C@H:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH3:11])[N:6]=3)[CH:26]=2)[CH2:24][CH2:23]1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 55 °C
Yield: 66.2 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 23, 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature was added 5-cyclopropyl -1H-pyrazol-3-amine (0.50 g, 4.0 mmol), and DIEA (0.26 g, 2.0 mmol). The reaction was then heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was then extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.53 g, 66%). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=11.1 Hz, 1H), 7.38-7.35 (m, 2H), 7.07-7.02 (m, 2H), 6.17 (s, 1H), 5.41-5.39 (m, 1H), 1.93-1.87 (m, 1H), 1.61 (d, J=7.0 Hz, 3H), 1.02-1.00 (m, 2H), 0.69-0.66 (m, 2H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]=1I.CC1CCCO1.C([Mg]Cl)(C)C.O1CCCC1.[Cl-].[NH4+]>>[I:1][C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(I)c(I)n2CCN2CCCC2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(I)cn2CCN2CCCC2)CC1
Temperature: 0 °C
Yield: 98 %

Procedure:
Combine tert-butyl 4-(4,5-diiodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (51.00 g, 84.96 mmol) and 2-methyltetrahydrofuran (357 mL). Cool the reaction mixture to 0° C. Add 2 M isopropylmagnesium chloride in tetrahydrofuran (55.22 mL, 1.3 eq) dropwise over 45 minutes, maintaining the temperature below 5° C. Add saturated aqueous ammonium chloride. Separate the layers. Wash the aqueous phase with methyl tert-butyl ether. Wash the organics with aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, decolor with charcoal, filter, and concentrate in vacuo to give tert-butyl 4-(4-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate as a yellow solid (39.50 g, 98%). MS (ES) m/z=475 [M]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[O:6][CH:7]=1.[C:12]([Mg]Br)#[CH:13].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:11][C:2]([F:10])([F:1])[C:3]1[CH:4]=[C:5]([CH:8]([OH:9])[C:12]#[CH:13])[O:6][CH:7]=1
Reactant: O=Cc1cc(C(F)(F)F)co1
Reactant: C#C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1cc(C(F)(F)F)co1

Procedure:
1.8 g of the product of Stage F were cooled to 0°/+5° C. in 20 ml of tetrahydrofuran and 24 ml of ethynylmagnesium bromide were added over 30 minutes. The mixture was allowed to return to room temperature and was then poured into a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract was dried and the solvent was evaporated to obtain 0.8 g of the expected product after chromatography on silica (eluent: methylene chloride).
Reaction SMILES: BrCCO.C12(C(Cl)=O)CC3CC(CC(C3)C1)C2.C(N(CC)CC)C.Br[CH2:26][CH2:27][O:28][C:29]([C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)=[O:30].[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[C:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:44][CH:43]=1>C(Cl)Cl>[F:61][C:58]1[CH:59]=[CH:60][C:55]([C:48]([C:45]2[CH:44]=[CH:43][C:42]([F:41])=[CH:47][CH:46]=2)=[C:49]2[CH2:54][CH2:53][N:52]([CH2:26][CH2:27][O:28][C:29]([C:31]34[CH2:40][CH:35]5[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]5)[CH2:32]3)[CH2:38]4)=[O:30])[CH2:51][CH2:50]2)=[CH:56][CH:57]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(OCCBr)C12CC3CC(CC(C3)C1)C2
Agent: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: OCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromoethanol (4.9 g., 0.04 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (5.6 g., 0.02 mol) and triethylamine (4 g., 0.04 mol) were added. The reaction mixture was stirred at room temperature overnight and the methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 12 g. of the intermediate adamantane-1-carboxylic acid bromoethyl ester. The title compound was prepared by stirring 4-[bis(4-fluorophenyl)-methylene]piperidine (2 g., 0.07 mol), adamantane-1-carboxylic acid bromoethyl ester (2.0 g., 0.007 mol) and triethylamine (1 g., 0.01 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf = 0.75 in 30% ethanol/ethylacetate system) was separated and converted to the hydrochloride salt with ethanolic HCl; mp. 249°-254° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccncc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-pyridyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-pyrid-4-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)[CH2:25][CH2:24]3)[N:10]=2)[CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Br)ccc2n1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Yield: 62.1 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (0.253 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.186 g), triethylamine (Aldrich; 0.104 g), and ethylene glycol (2 mL) give 0.249 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 110-112° C.; MS m/z 388, 390; IR (mineral oil) 1511, 1234, 1219, 1448, 1326 cm-1. 1H NMR (CDCl3) δ2.74, 3.16, 3.77, 6.87-6.98, 7.21, 7.48, 7.53, 8.24.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([O:48]C)=[O:47])=[CH:42][C:41]=2[CH3:50])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>CN(C=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([OH:48])=[O:47])=[CH:42][C:41]=2[CH3:50])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (29.8 mg, 0.168 mmol) in DMF (1.5 mL) was added t-BuOK (17.5 mg, 0.152 mmol). After 10 minutes, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (75 mg, 0.152 mmol) in DMF (1.5 mL) was added by cannula. The reaction was stirred for 30 minutes, and then quenched with saturated NH4Cl solution (10 mL), diluted with EtOAc (15 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was dissolved with MeOH (2 mL) and 4M KOH solution (0.5 mL) was added. The reaction was stirred at room temperature for 2 hours, then stored in the freezer for 16 hours. The reaction was warmed to room temperature, and stirred for 2 hours. The reaction was quenched with 1 N HCl solution (5 mL), diluted with EtOAc (15 mL), washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA), followed by lyophilization to afford 2″-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid LCMS=576.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 8.01-7.86 (m, 2H), 7.67-7.50 (m, 2H), 7.44-7.32 (m, 3H), 7.23-7.07 (m, 5H), 6.91-6.85 (m, 2H), 4.92-4.58 (m, 2H), 4.27 (d, J=15.6 Hz), 4.11 (d, J=15.6 Hz), 4.06-3.82 (m, 5H), 3.64-3.51 (m, 1H), 2.86-2.71 (m, 1H), 2.47-2.28 (m, 4H).
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:21][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCNC1CCC(Cc2ccccc2)(N(C)C)CC1

Procedure:
6.00 g 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in 90 ml analytical grade tetrahydrofuran, and 1.53 g n-propylamine followed by 3.36 ml glacial acetic acid were added, while stirring in an ice-bath. 7.68 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 45 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 50 ml diethyl ether each time. The combined organic phases were washed twice with 50 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (6.43 g) was chromatographed over silica gel with diethyl ether with the addition of five percent by volume of aqueous ammonia solution (25 wt. %). 707 mg of the nonpolar diastereoisomer of 1-benzyl-N,N-dimethyl-N′-propyl-cyclohexane-1,4-diamine were obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)=[CH:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ccc(Br)c2ccccc12
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c3ccccc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-bromonaphthalen-1-amine (1.0 g, 4.5 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.7 g, 5.4 mmol), Pd(PPh3)4 (26.01 mg, 0.02 mmol) and Na2CO3 (3.34 g, 31.5 mmol) in 10 mL of DMF and 5 mL of water was degassed and purged with nitrogen. The reaction was heated at 100° C. for 5 h, and cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography (MeOH/DCM: 5/95) to afford tert-butyl-4-(4-aminonaphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:25]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])[CH3:26])#[N:24]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4ccccc4)c3)c2cc1OC
Yield: 40.6 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (104 mg, 0.3 mmol) described in Example 308A to afford 1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (68.87 mg, 40%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.74 (s, 6H), 4.04 (s, 6H), 6.58 (s, 1H), 7.26-7.86 (m, 10H), 8.63-8.69 (m, 2H), 9.28 (s, 1H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: COCCl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 31.6 %

Procedure:
A mixture of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (4.5 g, 19.9 mmol), chloromethyl methyl ether (2.3 mL, 30.3 mmol), potassium carbonate (5.5 g, 39.8 mmol) and potassium iodide (0.66 g, 3.98 mmol) in N,N-dimethylformamide (50 mL) was stirred at 70° C. for 20 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-1:9) to give the title compound (1.7 g, yield 32%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[B].[C:25](N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.IC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:25])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Agent: [B]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Example 1) (50 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol/g) (113 mg) and N,N-dimethyl formamide (2 ml) was shaken at room temperature for 30 minutes. To the mixture was added iodomethane (28 mg), and the mixture was further shaken for 1 hour. After the resin was filtered off, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-hexane (1:1:4 to 1:1:0, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to isolate 2-(3-methoxyphenyl)-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (22 mg, 41%) (As a result of this reaction, a mixture of two isomers was obtained, and the isomer having higher polarity is the desired compound.)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]1[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][C:25]4[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COC(=O)C1CNCCN1Cc1cc(OC)c(OC)c(OC)c1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In dichloromethane (18 ml) is dissolved 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (1.44 g). The solution is added dropwise taking 5 minutes, while stirring at 0° C., to a mixture of methyl 1-(3,4,5-trimethoxybenzyl)piperazine-2carboxylate dihydrochloride (2.16 g), triethylamine (2.5 g) and dichloromethane (25 ml). The reaction mixture is stirred for one hour at room temperature, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone =3:3:1) to afford methyl 4-(2 3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -1-(3,4,5-trimethoxybenzyl)piperazine -2- carboxylate, which is identical with the product obtained in Working Example 25, as a colorless oily product (2.2 g).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:27][C@@H:28]1[CH2:33][C@@H:32]2[CH2:34][C@@H:30]([C:31]2([CH3:36])[CH3:35])[C@H:29]1[CH3:37].C(OCC)(=O)C>Cl.O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:27][C@@H:28]1[CH2:33][C@@H:32]2[CH2:34][C@@H:30]([C:31]2([CH3:36])[CH3:35])[C@H:29]1[CH3:37]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c1Br)C2(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCC3CCNCC3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl 4-[({[5-bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]piperidine-1-carboxylate (34.4 mg, 0.06 mmol) was dissolved in 4 M hydrogen chloride/1,4-dioxane (1 mL) and stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to give the desired product.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH3:43])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate. Yield: 41% of theory, C30H32N6O5 (556.6) Rf value: 0.85 (silica gel; dichloromethane/ethanol=4:1) ##EQU62##