Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[CH:18]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CCO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2/[CH:18]=[N:21]/[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1N2CC(CCC2/C=N/O)N1OCc1ccccc1
Yield: 42.3 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde (510 mg, 1.96 mmol), hydroxylamine hydrochloride (158 mg, 2.27 mmol) and pyridine (621 mg, 7.85 mmol) in EtOH (15 mL) was stirred at rt for 2 hrs. Then, the reaction mixture was concentrated and the residue was diluted with DCM (25 mL), washed with water (3×), and saturated sodium chloride, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (3:1 to 3:2 petroleum ether/EtOAC) to afford (E)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde oxime (228 mg, 42%) as a white solid. ESI-MS (EI+, m/z): 276 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
4-Dimethylaminopyridine (2.55 g, 21.3 mmol) and triethylamine (46.9 ml, 340.8 mmol) in dichloromethane (100 ml) are added to a solution of (S)-(−)-4-benzyl-2-oxazolidinone (37.7 g, 213 mmol) in dichloromethane (300 ml). Next, isovaleroyl chloride (33.75 ml, 207 mmol) in dichloromethane (50 ml) is added to the previously prepared mixture and cooled to 0° C. keeping the internal temperature below 10° C. The reaction mixture is stirred for 30 minutes at 10° C., then the formed salts are filtered. Water (100 ml) is added and the phases are separated. The organic phase is washed with water (100 ml) and brine (100 ml), dried over sodium sulphate and evaporated to dryness obtaining 53 g of a yellow oil, which solidifies over time (yield 95%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH3:30][C:31]([CH3:36])=[CH:32][C:33](Cl)=[O:34]>CN(C)C(=O)C>[CH3:26][N:25]1[C:21]([C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]4[N:6]([CH:29]=[C:3]([NH:2][C:33](=[O:34])[CH:32]=[C:31]([CH3:36])[CH3:30])[N:4]=4)[N:7]=3)[CH:13]=[CH:14][C:15]=2[CH3:28])=[O:20])=[CH:22][C:23]([CH3:27])=[N:24]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)=CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 68 %

Procedure:
In the same manner as in Example 264 and using N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), 3-methylbut-2-enoylchloride (81 μL, 0.73 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (150 mg, 68%) was obtained as a pale-yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([CH3:24])[C:21](=[O:22])[N:12]2[CH2:13][CH:14]=[CH:15][CH:16]([C:17]([O:19][CH3:20])=[O:18])[N:11]2[C:10]1=[O:23].Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1([CH3:24])[C:21](=[O:22])[N:12]2[CH2:13][CH:14]=[CH:15][CH:16]([C:17]([O:19][CH3:20])=[O:18])[N:11]2[C:10]1=[O:23])(=[O:4])=[O:3]
Reactant: COC(=O)C1C=CCN2C(=O)C(C)(CCO)C(=O)N12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCOS(C)(=O)=O)C(=O)N12
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
3.45 g (30 mmol) of methanesulfonyl chloride were added dropwise to a stirred solution, cooled at 0° C., of 6.7 g (25 mmol) of methyl 2,3,5,8-tetrahydro-2-(2-hydroxyethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate in 20 ml of dry pyridine. After 2 hours, the resulting suspension was poured on to ice/water and acidified with 2M hydrochloric acid. Extraction with dichloromethane then yielded 7.84 g (75%) of methyl 2,3,5,8-tetrahydro-2-(2-methanesulfonyloxyethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 104°-105° C. (from diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (74.1 mg, 65%).
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].Cl.C(=N)(OCC)C.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([O:30][S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])(=[O:33])=[O:32])[CH:26]=[C:27]([CH3:29])[CH:28]=2)[CH2:17][CH2:16]1>CN(C)C=O>[ClH:40].[C:1]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([O:30][S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])(=[O:32])=[O:33])[CH:26]=[C:27]([CH3:29])[CH:28]=2)[CH2:17][CH2:16]1)(=[NH:3])[CH3:2]
Reactant: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=N)N1CCC(COc2cc(C)cc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Triethylamine (0.5 mL) and ethyl acetimidate hydrochloride (247 mg, 2.0 mmol) were added to a solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature overnight. The N,N-dimethylformamide was removed in vacuo and the residue partitioned between methylene chloride (200 mL) and 10% K2CO3 (50 mL). The organic phase was washed with 10% K2CO3 (2×50 mL) and dried over K2CO3. The solvent was removed in vacuo, HCl-methanol (30 mL) was added, and the solution was concentrated in vacuo. The residue was crystallized from methanol-ethyl acetate to give the title compound as white crystals (405 mg, 86%). 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (m, 2 H), 1.82 (d, 2 H, J=7.0 Hz), 2.05 (m, 1 H), 2.20 (s, 3 H), 2.29 (s, 3 H), 3.16 (m, 2 H), 3.77 (d, 2 H, J=3.0 Hz), 3.92 (d, 1 H, J=6.5 Hz), 4.17 (d, 1 H, J=6.5 Hz), 6.46 (d, 1 H, J=2.5 Hz), 6.49 (s, 1 H), 7.59 (t, 1 H. J=8.0 Hz), 7.87 (m, 2 H), 7.95 (d, 1 H, J=8.0 Hz), 8.77 (br s, 1 H), and 9.35 (br s, 1 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H25N2O4SCl: 437.1 (M+H). Found: 436.8.
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[CH2:14][CH:13]([OH:15])[CH2:12]1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22]([Cl:34])=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>CN(C=O)C.O>[Cl:34][C:22]1[N:21]=[N:20][C:19]([O:15][CH:13]2[CH2:12][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:14]2)=[C:24]([N:25]2[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[CH:23]=1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Reactant: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C1CCN(c2cc(Cl)nnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 0.78 g, 3.8 mmol) in DMF (20 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at room temperature for 10 min and then 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.1 g, 2.6 mmol, 70% yield) as white solid. ESI-MS (M+1): 438 calc. for C24H25ClN4O2 437.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: NCc1ccccc1Cl
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)NCc2ccccc2Cl)c1

Procedure:
25.5 g of 4'-chloro-3'-chlorosulfonylacetophenone were reacted with 16 g of o-chloro-benzyl amine and 25.5 g of triethyl amine and worked up. Colorless crystals from isopropanol (active charcoal), melting point: 102° C.
Reaction SMILES: [CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[NH:43][N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:51](Cl)([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43]([C:51]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[N:42]=[N:41][N:40]=3)=[CH:31][CH:32]=2)[C:8]2[CH:9]([C:21]([O:23][CH3:24])=[O:22])[N:10]([C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a mixture of methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.0 g), triethylamine (0.69 g) and chloroform (20 ml) is added trityl chloride (1.43 g), and the mixture is stirred at room temperature for 30 minutes. The reaction solution is washed, dried, and evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; ethyl acetate/n-hexane) to give methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.29 g) as needles. m.p. 124°-126° C. (decomposed)
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.CI.[C:11](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Br:1][C:2]1[N:3]([CH3:11])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1
Reactant: Clc1nc(Br)[nH]c1Cl
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1c(Br)nc(Cl)c1Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-4,5-dichloroimidazole (1 g, 4.6 mmol), methyl iodide (346 μL, 5.56 mmol), potassium carbonate (1.27 g, 9.2 mmol) and tetrabutylammonium bromide (148 mg, 0.46 mmol) in acetonitrile (2 mL) was stirred vigorously at 70-80° C. for 1.0 h. After cooling to room temperature, the inorganic salts were filtered off and washed with acetonitrile. The filtrate was evaporated and the residue was purified by flash chromatography (Si) to afford 2-bromo-4,5-dichloro-1-methyl-1H-imidazole as a white solid. LCMS calc.=230.89; found=230.9 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 3.61 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][C:16]#[N:17]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[C:15](=[CH:5]/[C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)/[C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cccc(F)c1
Product: COc1ccc(/C(C#N)=C/c2cccc(F)c2)cc1OC
Yield: 15.3 %

Procedure:
3-Fluorobenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (2.9 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (0.7 g, yield: 15%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[O:8][C:4]=2[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:14])[O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2[nH]c(=S)oc2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nc2ccc(C)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl-1,3-benzoxazole-2(3H)-thione (375 mg, 2.27 mmol) was dissolved in THF (2.0 mL), and iodomethane (1610.8 mg, 11.35 mmol) and potassium carbonate (627.36 mg, 4.54 mmol) were added. This reaction mixture was stirred vigorously at rt overnight. The reaction mixture was filtered and the solid was rinsed with additional THF. The filtrate was concentrated in vacuo to a yellow solid. The solid was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried with MgSO4, and concentrated. The solid was dried for 1 h in a 50° C. oven. The product 6-methyl-2-(methylsulfanyl)-1,3-benzoxazole was obtained as yellow-solid (145 mg, 35.6%). 1H NMR (300 MHz, DMSO-d6) δ 7.50 (d, 1H), 7.20 (s, 1H), 7.10 (d, 1H), 2.78 (s, 3H), 2.42 (s, 3H); LC-MS ret. time 2.90 min (method 2), m/z 180.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30]([NH:32][CH:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[O:31])=[N:27][CH:26]=2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:29][C:28]([C:30]([NH:32][CH:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[O:31])=[N:27][CH:26]=3)=[CH:21][CH:20]=2)=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3Oc3ccccc3)cc2)o1)C(C)C
Yield: 79 %

Procedure:
The title compound was synthesized analogous to Example 1, using 4-chloro-1-isocyanato-2-phenoxybenzene and intermediate 1. Yield 79%; 1HNMR (DMSO-d6, 300 MHz): δ 9.61 (s, 1H), 8.99 (d, 1H), 8.74 (s, 1H), 8.4 (d, 1H), 7.8 (s, 1H), 7.77 (d, 2H), 7.6 (d, 2H), 7.44 (d, 2H), 7.22 (dd, 1H), 7.1 (d, 2H), 7.0 (dd, 1H), 6.85 (d, 1H), 4.3, (m, 1H), 3.67 (s, 3H), 2.28 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 563 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1.[H-].[Na+].I[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[N:15]3[CH3:25])=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)NC(=O)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1CC1COC(C)(C)O1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
300 mg of 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 6 ml of N,N-dimethylformamide. While cooling on ice, 49 mg of 60% sodium hydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 0.29 g of iodomethane was added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 310 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:18]1([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:22]=[N:21][N:20]=[N:19]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([N:18]4[CH:22]=[N:21][N:20]=[N:19]4)=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-n2cnnn2)cc1
Product: O=C(c1ccc(-n2cnnn2)cc1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.05 min; Mass spectrum (ESI+): m/z=425 [M+H]+.
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18]([O:20]CC)=O)[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].Cl.[C:34](=[NH:37])([NH2:36])[CH3:35].CO.C[O-].[Na+]>CO>[F:32][C:29]1[CH:30]=[CH:31][C:6]2=[C:7]([CH:28]=1)[O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:20])[NH:37][C:34]([CH3:35])=[N:36][C:23]=3[CH2:24][CH2:25][CH3:26])[CH:13]=[CH:12][C:11]=1/[C:5]/2=[C:3](/[CH3:4])\[C:1]#[N:2]
Reactant: CC(=N)N
Reactant: CCCC(=O)C(Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
[step 2] (E)-ethyl 2-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-3-oxohexanoate (1.18 g, 2.71 mmol) obtained in step 1 was dissolved in methanol (14 mL), acetimidamide hydrochloride (640 mg, 6.77 mmol) and 28% sodium methoxide methanol solution (1.83 mL, 9.48 mmol) were added, and the mixture was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure, methanol was added to the obtained residue, and the precipitated crystals were collected by suction filtration to give (E)-2-{3-fluoro-8-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (960 mg, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O>C1COCC1.[H][H].[Pd]>[NH2:1][C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: N#Cc1cc(N2CCOCC2=O)ccc1N
Yield: 60 %

Procedure:
2-Nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile (1.1 g) was dissolved in THF (80 ml) and hydrogenated with hydrogen (1 atm) over Pd/C 10% (350 mg) for 18 h at 25° C. The reaction mixture was then filtered through decalite and precipitated (AcOEt/heptane) to yield 2-amino-5-(3-oxo-morpholin-4-yl)-benzonitrile as a white solid (580 mg). MH+=218.4
Reaction SMILES: O1[CH:5]2[C:6]3[C:7]4[C:12]([C:13]5[C:18]([C:19]=3[CH:2]1[CH:3]=[CH:4]2)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:11][CH:10]=[CH:9][CH:8]=4.I[C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.IC1C=C(C=CC=1)CP(=O)(OCC)OCC.C(N(CC)CC)C>[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:5]1[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:2]=[CH:3][C:4]=1[C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1
Reactant: CCOP(=O)(Cc1ccc(I)cc1)OCC
Reactant: C1=CC2OC1c1c2c2ccccc2c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOP(=O)(Cc1cccc(I)c1)OCC
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1)OCC
Temperature: 110 °C
Yield: 70 %

Procedure:
Compound A (760 mg, 3.11 mmol), zinc (1.85 g, 28.2 mmol), and PdCl2(PPh3)2 (198 mg, 0.28 mmol) were charged in a two-necked bottle. The bottle was then vacuumed and purged with nitrogen, and dried toluene (30 mL), diethyl 4-iodobenzylphosphonate (0.65 mL, 2.82 mmol) or diethyl 3-iodobenzylphosphonate, and triethyl amine (3.91 mL, 28.2 mmol) were added to the bottle. The mixture in the bottle was heated to 110° C. for reaction for 48 hours, and the resulting was filtered to remove metal. The filtrate was condensed to remove the solvent, and then purified by column chromatography (ethyl acetate/hexanes=½) to obtain E (0.90 g, yield=70%) as white solid.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=1.[CH3:14][O:15][Si:16](OC)([O:19][CH3:20])[O:17][CH3:18]>O1CCCC1>[CH3:10][N:9]([C:8]1[CH:12]=[CH:13][C:5]([Si:16]([O:19][CH3:20])([O:17][CH3:18])[O:15][CH3:14])=[CH:6][CH:7]=1)[CH3:11]
Reactant: CO[Si](OC)(OC)OC
Reactant: CN(C)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CO[Si](OC)(OC)c1ccc(N(C)C)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
In a 200 ml two-necked flask equipped with a dropping funnel were put 1.01 g (41.5 mmol) of magnesium, 50 ml of tetrahydrofuran (THF), and a small amount of iodine in a nitrogen stream, and a solution of 8.32 g (41.6 mmol) of p-bromo-N,N-dimethylaniline in 50 ml of THF was added thereto dropwise at room temperature over a 40-minute period while stirring. After the addition, the mixture was stirred at room temperature for 75 minutes, and a solution of 6.40 g (42.0 mmol) of tetramethoxysilane in 60 ml of THF was further added thereto, followed by stirring at room temperature overnight. The solvent was removed under reduced pressure, and the residue was suspended in 100 ml of toluene and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound in a yield of 75%.