Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[C:30]([NH2:31])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[NH2:31][C:30]1[CH:29]=[C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:27]=[N:26][C:25]=1[CH3:24]
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one Intermediate K) and 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (Stage 88.1.1) to give the title compound as a white solid. (HPLC: tR 2.14 min (Method A); M+H=420 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.38 (s, 1H), 8.13-8.10 (m, 1H), 7.80-7.77 (m, 1H), 7.75-7.73 (m, 1H), 7.48-7.47 (m, 1H), 7.08-7.06 (m, 1H), 5.21-5.16 (m, br, 2H), 3.99 (s, 3H), 3.59 (s, 3H), 2.30 (s, 3H))
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9](#[N:11])[CH3:10].[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:21]=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[OH:22][C@H:21]([C@@H:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:10][C:9]#[N:11]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CC#N
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
To a solution of lithium diisopropylamide (4.40 mmol) in dry tetrahydrofuran (4 mL) at -78° C. was added acetonitrile (0.25 mL, 4.4 mmol). To this enolate suspension was added 2(S)-t-butyloxycarbonylamino-3-cyclohexylpropanal (0.76 g, 2.98 mmol) in tetrahydrofuran (5 mL) pre-cooled to -78° C. After stirring for 15 minutes, the mixture was quenched with 2M HCl (5.0 mL), and extracted with ether which was dried over MgSO4 and evaporated. Flash chromatography on silica gel with ethyl acetate/hexane mixtures afforded 0.360 g (41%) of the desired compound as an oil.
Reaction SMILES: CS(Cl)(=O)=O.C([CH:8]1[C:12](O)([C:13]([OH:15])=[O:14])[C:11]2[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH2:20][C:10]=2[O:9]1)C.[CH2:23](N(CC)CC)[CH3:24].[OH-].[Na+]>ClCCl>[O:22]=[C:17]1[C:11]2[C:12]([C:13]([O:15][CH2:23][CH3:24])=[O:14])=[CH:8][O:9][C:10]=2[CH2:20][CH:19]([CH3:21])[CH2:18]1
Reactant: CCC1OC2=C(C(=O)CC(C)C2)C1(O)C(=O)O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of methanesulfonyl chloride (6.1 mL, 78.5 mmol) in dichloromethane (50 mL) was added to a stirring solution of ethyl 3-hydroxy 4-oxo-6-methyl-2,3,4,5,6,7-hexahydrobenzofuran-3-carboxylic acid (18.48 g, 76 mmol) and triethylamine (21.4 mL, 154 mmol) in dichloromethane (150 mL) at 0° C. The mixture was allowed to reach ambient temperature, stirred for 2 hours, then poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (16.86 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([O:26]CC)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([OH:26])=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(=O)O)CC1
Yield: 96.9 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-ethoxycarbonylnitrobenzene (1.0 g) in ethanol (10 ml) was added aqueous potassium hydroxide solution (0.2 g in 0.5 ml) and the mixture was heated under reflux for 2 hours. After neutralization with 1M hydrochloric acid, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the desired compound (0.9 g, yield 96%) as a yellow solid.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:29])[CH2:10]1>N1C=CC=CC=1>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:29])[CH2:10]1
Reactant: CC(=O)OC(C)=O
Agent: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (16.6 g, 162.8 mmol) is added to a solution of Compound 1.14 (33.0 g, 108.55 mmol) in pyridine (150 mL) at 0° C. under an inert atmosphere. The resulting reaction mixture is stirred overnight at ambient temperature. Upon completion of the reaction, as evidenced by TLC, pyridine and remaining acetic anhydride are removed under vacuum. The crude residue is diluted with ethyl acetate (500 mL) and washed with water (3×150 mL), saturated brine solution (100 mL) and dried over MgSO4 (75 g). The solvent is evaporated under vacuum and the crude material is purified by column chromatography [59(W)×800(L) mm, 60-120 Mesh silica, 150 g], eluting with ethyl acetate/hexane (1:10) [25 mL fractions, 10 mL/min elution, monitored by TLC with p-anisaldehyde charring; Rf for Compound 1.15=0.38 and Rf for Compound 1.14=0.1 in EtOAc/Hexane (3:7)] to afford Compound 1.15 (19.0 g, 66.4% yield) as a colorless solid. Table 4 describes the measured properties of the product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[ClH:17].[CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:14])=[CH:15][CH:16]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)nc1C
Yield: 79.5 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (422 mg) described in Preparation Example 37 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (483 mg) described in Preparation Example 52, the title compound (675 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]([C:34]1[S:35][CH:36]=[C:37]([C:39](=[O:42])[NH:40][CH3:41])[N:38]=1)[CH2:3][CH:4]([N:8]([CH2:26][O:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])[C:9](=[O:25])[CH:10]([NH:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH3:24])=[O:17])[CH:11]([CH3:14])[CH2:12][CH3:13])[CH:5]([CH3:7])[CH3:6].[C:43](OC(=O)C)(=[O:45])[CH3:44]>N1C=CC=CC=1>[C:43]([O:1][CH:2]([C:34]1[S:35][CH:36]=[C:37]([C:39](=[O:42])[NH:40][CH3:41])[N:38]=1)[CH2:3][CH:4]([N:8]([CH2:26][O:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])[C:9](=[O:25])[CH:10]([NH:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH3:24])=[O:17])[CH:11]([CH3:14])[CH2:12][CH3:13])[CH:5]([CH3:7])[CH3:6])(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(COC(=O)CC(C)C)C(CC(O)c1nc(C(=O)NC)cs1)C(C)C
Solvent: c1ccncc1
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(COC(=O)CC(C)C)C(CC(OC(C)=O)c1nc(C(=O)NC)cs1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
A 0.10 M solution of 13c (10.5 mg, 0.0172 mmol) in pyridine (0.172 mL) was cooled to 0° C., and acetic anhydride (8.10 μL, 0.0861 mmol) was added. The reaction mixture was allowed to warm to rt over 2 h and was stirred at rt for 24 h. The solvent was removed under reduced pressure. Column chromatography (100:0 to 90:10 CH2Cl2:MeOH) afforded 10.1 mg (90%) of 4 as an amorphous solid. [α]D23=+60.5 (c=0.6, MeOH). IR: 1229, 1371, 1420, 1466, 1499, 1549, 1665, 1742, 2792, 2848, 2875, 2934, 2961, 3305, 3380 cm−1. 1H NMR (500 MHz, MeOD): δ 0.78 (d, 3H, J=7.0 Hz), 0.84 (d, 3H, J=6.7 Hz), 0.87-0.91 (m, 6H), 0.96 (d, 3H, J=6.7 Hz), 1.04 (d, 3H, J=6.3 Hz), 1.25-1.15 (m, 1H), 1.24-132 (m, 1H), 1.48-1.65 (m, 4H), 1.72-1.75 (m, 2H), 1.79-1.86 (m, 1H), 1.93-2.18 (m, 5H), 2.13 (s, 3H), 2.15 (s, 3H), 2.22-2.29 (m, 1H), 2.47-2.57 (m, 2H), 2.89-2.94 (m, 1H), 2.92 (s, 3H), 4.43 (br s, 1H), 4.60 (d, 1H, J=10.1 Hz), 5.39 (d, 1H, J=12.2 Hz), 5.87 (d, 1H, J=12.0 Hz), 6.18 (d, 1H, J=12.5 Hz), 8.16 (s, 1H). 13C NMR (125 MHz, MeOD) δ 10.7, 16.4, 20.3, 20.69, 20.74, 22.68, 22.69, 24.3, 25.6, 26.1, 26.3, 26.6, 31.5, 32.2, 35.9, 37.3, 44.2, 44.7, 55.0, 56.6, 70.4, 70.7, 125.5, 150.7, 163.8, 170.8, 171.9, 173.3, 175.5, 176.7. HRMS (FAB) calcd for C32H54N5O7S (M+H): 652.3744. Found: 652.3719.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCc1ccc(F)cc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(4-Fluoro-benzyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.25 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.33 mmol of 4-fluoro-benzylamine. LC/MS [6.99 min; 466 (M+1)]
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>CN(C)C=O>[CH2:1]([N:8]1[C:18]2[C:13](=[C:14]([O:19][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: O=C1CCc2c(O)cccc2N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCCCN3CCN(c4ccccc4)CC3)cccc2N1Cc1ccccc1
Yield: 46.7 %

Procedure:
2.5 grams of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and 0.48 g of 50% oily NaH are mixed with 30 ml of dimethyl formamide and stirred, then 4 g of 1-chloro-3-(4-phenylpiperazinyl)propane are added therein and warmed to 50°-60° C. for 2.5 hours. The reaction mixture is concentrated under a reduced pressure and the residue thus obtained is extracted with chloroform. After removing the chloroform by distillation, the thus obtained residue is recrystallized from ligroin to obtain 2.1 g of 1-benzyl-5-[3-(4-phenylpiperazinyl)-propoxy]-3,4-dihydrocarbostyril in the form of pale yellowish needle-like crystals with a melting point of 113° C.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCC1
Reactant: O=C(O)c1cccnc1S
Product: O=C(O)c1cccnc1SC1CCCC1

Procedure:
2-Mercapto-nicotinic acid (1.0 g, 6.44 mmol) and bromo-cyclopentane (2 mL, 19.33 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:26])[CH2:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:26])[CH2:15][S:16]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:17])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CS(=O)(=O)Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CS(=O)(=O)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylmethanesulfonyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18](=[O:28])[C:19]([NH:21][C:22]3[CH2:23][O:24][C:25](=[O:27])[CH:26]=3)=[O:20])=[CH:10]2)=[CH:6][CH:5]=1.[CH3:31]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18](=[O:28])[C:19]([N:21]([CH3:31])[C:22]3[CH2:23][O:24][C:25](=[O:27])[CH:26]=3)=[O:20])=[CH:10]2)=[CH:29][CH:30]=1
Reactant: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12)C1=CC(=O)OC1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, sodium hydride (10 mg of a 60% wt/wt suspension in mineral oil) is added to a solution of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(5-oxo-2,5-dihydro-3-furanyl)acetamide (100 mg) in dry DMF (2 ml). After 20′, methyl iodide (0.016 ml) is added. After 3 h the solvent is removed by roto-evaporation and the obtained residue is partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The obtained residue is suspended in boiling MeOH/i-PrOH 1/1. After cooling to room temperature the insoluble material is collected by filtration and oven-dried at 60° C. for 3 h, to give 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-methyl-2-oxo-N-(5-oxo-2,5-dihydro 3-furanyl)acetamide (52 mg).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](O)=[O:26].O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[Cl:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25]([NH:17][C:14]1[S:15][C:16]2[C:8]([CH:6]3[CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:7]3)=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[N:13]=1)=[O:26]
Reactant: O=C(O)c1ccnc(CCl)c1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 2-chloromethyl-isonicotinic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as brown solid. MS: m/e=435(M+H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([CH3:35])=[O:34].OO.CC[O:40]C(C)=O>C(O)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([CH3:35])(=[O:40])=[O:34]
Reactant: CCOC(C)=O
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)=O)cc(OC)c21
Agent: OO
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3S(C)(=O)=O)cc(OC)c21
Temperature: 25 °C

Procedure:
A mixture of 140 mg (0.252 mmol) of 4-Bromo-2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-benzyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole and 30 μl (0.265 mmol) hydrogen peroxide solution (30%) in 3 ml acetic acid is stirred at reflux temperature for 3 h. After that the reaction mixture is allowed to cool to room temperature and 25 ml EtOAc are added and this solution is washed with 4n NaOH (2×), water and sodiumhydrogensulfite solution, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 112 mg of the title compound as pale red crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(=O)[C:47](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:46]([C:61]3C=CC(S(C)(=O)=O)=CC=3)[CH:45]=N2)C=CC=1.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:45][CH:46]([CH3:61])[CH3:47])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Agent: N
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375) in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (yield: 0.486 g, 100%). mp 121-128° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 417 (M+H)+, 434 (M+NH4)+; Anal. calc. for C21H21FN2O4S.0.50H2O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H, 4.97; N, 6.34
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH2:7]1)(=O)=O.[C:31]([O-:34])(=[S:33])[CH3:32].[K+]>CN(C)C=O>[C:31]([S:33][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH2:7]1)(=[O:34])[CH3:32]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.84 g) in dimethylformamide (40 ml) was added potassium thioacetate (0.95 g) and the mixture was stirred at 70°-80° C. for 2 hours. The reaction mixture was poured into ice-water (200 ml) and extracted 3 times with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.23 g).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH2:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([NH2:42])=[CH:41][C:34]=2[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[CH:39][C:40]([NH:42][C:2]3[N:23]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH2:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:41][C:34]=2[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
7-[8-(2-Ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.640 g, 1.87 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.590 g, 2.25 mmol) in a manner analogous to Example 311b to give product (1.06 g, 99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.42 (m, 2H), 7.35 (d, 1H), 7.08 (t, 1H), 7.00 (d, 1H), 4.15 (q, 2H), 3.42 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H), 1.22 (t, 3H): MS=568 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.FC1C=CC(C2N=[C:42](C3CCNCC3)[N:43]([CH2:45]CN(C)C)[CH:44]=2)=CC=1C(F)(F)F>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:42][N:43]([CH3:45])[CH3:44])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=503, obsd.=503).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[C:2]([F:1])=[CH:3][C:4]([OH:11])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: BrBr
Reactant: O=C(O)c1ccc(F)cc1O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c(F)cc1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
4-Fluoro-2-hydroxybenzoic acid (29.01 g, 0.186 mol) was dissolved in acetic acid (290 ml), then a solution of bromine (31.18 g, 0.195 mol) dissolved in acetic acid (15 ml) was gradually dropwise added at room temperature (1 hour). After stirred at 60° C. for 24 hours, this was cooled to room temperature. The reaction liquid was dried to solidness under reduced pressure, the residue was dissolved in methanol (100 ml), and this was poured into water (600 ml). After stirring at room temperature for 15 minutes, the precipitated crystal was washed and collected by filtration, and dried to obtain the entitled compound (35.36 g, 93%) as a colorless solid.