Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[C:9](Br)[CH:10]=3)[CH:3]=1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[CH:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[CH2:16][C:14]([C:13]=2[C:12]=34)=[CH:15][CH:2]=1
Reactant: Brc1cc2c3c(c1)Cc1cc(Br)cc(c1-3)CC2
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Yield: 147.4 %

Procedure:
2,6-dibromo-8,9-dihydro-4H-cyclopenta[def]phenanthrene (4.45 g, 12.7 mmol) in a 250 ml round bottom flask was dissolved with xylene, and o-chloranil (4.15 g) was added thereto at room temperature. The reaction mixture was heated and refluxed in an oil bath for 72 hours. After the reaction was terminated, the reaction solution was cooled and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (mobile solvent: n-hexane) to give a compound 1 (3.6 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[CH:14]OC)[C:8]2=O.S(O)(O)(=O)=O.[CH3:22][S:23][C:24](=[NH:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:14]=[N:25][C:24]([S:23][CH3:22])=[N:26][C:8]=3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC=C1CCc2c(OC)cccc2C1=O
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc2c1CCc1cnc(SC)nc1-2
Yield: 72.5 %

Procedure:
To a solution of 5-methoxy-2-methoxymethylene-1-tetralone (9.78 g) in tetrahydrofuran (200 ml) was added 2-methyl-2-thiopseudourea sulfate (8.34 g), followed by potassium carbonate (9.7 g), and the mixture was refluxed overnight. Solvent was then removed under reduced pressure, the residue stirred with diethyl ether, and filtered. Concentration of the filtrate gave a brown solid, which upon crystallization from ethanol gave 7-methoxy-2-methylthio-5,6-dihydrobenzo[h]quinazoline (8.3 g) as a light brown solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[O:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:23]([C@@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[O:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of tert-butyl 3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.5 g) in acetic acid (1 ml) is added 30% hydrogen bromide-acetic acid solution (2 ml). The resulting mixture is allowed to stand for 1 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (20 ml). The solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (4 ml), the mixture is chromatographed on MCI gel using water-methanol (1:2) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(S)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.23 g) as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2F)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2F)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
Into a sealable vial, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[(2-fluorophenyl)methyl]-6-methyl-3-piperidinecarboxamide (189 mg, 0.409 mmol), EtOH (5 mL), Hunig's base (0.071 ml, 0.409 mmol), and hydrazine anhydrous (0.077 mL, 2.452 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (80 mg) as a light yellow solid. LC-MS (ES) m/z=475 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.8 Hz, 3H), 1.66 (m, 2H), 1.76 (m, 1H), 1.84 (m, 1H), 2.35 (m, 1H), 2.85 (m, 1H), 4.22-4.47 (m, 3H), 5.38 (s, 2H), 6.08 (s, 2H), 6.59 (s, 1H), 7.14-7.25 (m, 2H), 7.28-7.41 (m, 2H), 7.57 (m, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.45-8.54 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.O=C1N(C2CCNCC2)[C:25]2C=CC=C[C:24]=2N1.BrCC(OCC)=O>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:24][CH3:25])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and L=(N-methylene)piperidin-4-yl are prepared from β-aminotetralins (VII) or phenethylamines (XI) and [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid (Schemes 6–7). For example, 4-(2-keto-1-benzimidazolinyl)piperidine is reacted with a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diusopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. This carboxylic acid is reacted directly with βaminotetralins (VII) or phenethylamines (XI), in the presence of an amine base, under peptide coupling conditions described above, to afford benzimidazolinones (XVII) and (XVIII) of formula A in which Y=carbonyl and L=(N-methylene)piperidin-4-yl (Schemes 6–7).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(Cl)Cl.O>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
5-[2-fluoro-4-(1H-tetrazol-1-yl)-phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DCM (5 ml) and added TEA (60 mg, 0.6 mmol) and stirred the mixture at rt for 30 mins. To this mixture added methanesulphonyl chloride (14 mg, 0.12 mmol) and stirred at rt for 2 h. Work up (DCM/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (7:3) as eluent afforded the titled compound (17 mg) as a brown solid. M. P.: 209-212° C. MS (m/z): 443.2 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[S:13](=[O:15])(=[O:14])[N:12]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:30]1CCNS1(=O)=O)C1C=CC=CC=1>>[ClH:1].[CH2:2]([N:9]1[S:13](=[O:15])(=[O:14])[N:12]([C:16]2[CH:17]=[CH:18][C:19]([NH:20][NH2:30])=[CH:21][CH:22]=2)[CH2:11][CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)S2(=O)=O)cc1
Agent: Cl
Product: NNc1ccc(N2CCN(Cc3ccccc3)S2(=O)=O)cc1

Procedure:
The title compound was prepared from 4-(5-benzyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)aniline hydrochloride by a similar method to that described for Intermediate 1 (step 1); pale brown solid; δH (250 MHz, DMSO-d6) 7.42-7.32 (5H, m, Ph), 7.24 (2H, d, J=8.5 Hz, Ar--H), 7.02 (2H, d, J=8.5 Hz, Ar--H), 4.24 (2H, s, PhCH2 --), 3.68 (2H, t, J=6.4 Hz, --CH2 --), 3.39 (2H, t, J=6.4 Hz, --CH2 --).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C@H:8]([NH:17][CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][NH:27][C:26]=2[N:25]=1)[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:16][O:15][C:12]1[N:13]=[CH:14][C:9]([C@@H:8]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:7][C:6]([OH:41])=[O:5])=[CH:10][CH:11]=1
Reactant: COc1ccc([C@H](CC(=O)OC(C)(C)C)NCCN(CCCc2ccc3c(n2)NCCC3)C(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H](CC(=O)O)NCCNCCCc2ccc3c(n2)NCCC3)cn1

Procedure:
A solution of 3-1 (0.8 g, 1.34 mmol) in 3mL trifluoroacetic acid was stirred at 60° C. for 20 minutes and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 5% MeOH/93% CH2Cl2/2% NH3.H2O to 15% MeOH/83% CH2Cl2/2% NH3.H2O) to afford the desired product 3-2 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C(=O)NNC(=O)OC(C)(C)C
Yield: 86.4 %

Procedure:
A solution of 4-chloro-2-methoxybenzoic acid (4.3 g, 23.1 mmol), tert-butyl carbazate (3.5 g, 26.5 mmol), EDCI.HCl (5.0 g, 26.1 mmol), and triethylamine (3.5 mL, 2.6 g, 25.3 mmol) in CH2Cl2 (50 mL) was stirred at room temperature overnight. The next day the reaction was diluted with EtOAc (200 mL), then washed with IM H3PO4, saturated NaHCO3, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under vacuum, giving the product (6.0 g, 87%). MS (DCI) m/e 301 & 303 (M+H)+, 318 & 320 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ 9.40 (br s, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.08 (dd, J=8.2, 1.7 Hz, 1H), 6.98 (d, J=1.7 Hz, 1H), 6.67 (v br s, 1H), 4.00 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of 1,4-dichloro-2-nitrobenzene (20.0 g, 104.2 mmol) and methyl 4-hydroxybenzoate (15.85 g, 104.2 mmol) in 150 mL of EtOH was treated with Na2CO3 and heated overnight under reflux. Cooled to room temperature and quenched with water. Extracted with EtOAc. Dried over MgSO4, filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 10% EtOAc/hexane giving the title compound as a yellow solid (29.6 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:25][N:26]([CH:33]([CH3:35])[CH3:34])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][CH2:20][N:19]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:25])[CH:33]([CH3:35])[CH3:34])[CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
The title compound was synthesized in analogy to Example 89 from N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-4-amine from Example 82A (100 mg, 0.27 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (74 mg, 0.38 mmol) to yield 71 mg (50%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH2:28][OH:29]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH2:28][OH:29])=[O:13])[CH2:8]2
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCC[C@H]1CO

Procedure:
5-((S)-2-Hydroxymethyl-pyrrolidin-1-y1)-1-phenyl- 1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and L-prolinol. Mass spectrum (ES) MH+=421.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:23][CH:24]([C:26]1[S:30][C:29]([CH:31]=[O:32])=[N:28][CH:27]=1)[CH3:25].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[OH:23][CH:24]([C:26]1[S:30][C:29]([C:31](=[O:32])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:28][CH:27]=1)[CH3:25]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(O)c1cnc(C=O)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Yield: 76.6 %

Procedure:
A mixture of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 5-(1-hydroxyethyl)-1,3-thiazole-2-carbaldehyde (0.28 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.57 g, yield 75%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 480 (MH+).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]3[C:21]([O:32][CH3:33])=[CH:22][CH:23]=[C:24]([C:25]4[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=4)[C:14]=3[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4]>CN(C=O)C>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]3[C:21]([O:32][CH3:33])=[CH:22][CH:23]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:17][CH2:18][O:19][CH3:20])[CH:26]=4)[C:14]=3[N:13]=2)=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(-c3cccc(O)c3)ccc(OC)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(-c2ccc(OC)c3c2nc(-c2ccc(C(C)C)cc2)n3CCOC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 170.5 %

Procedure:
5 mg (0.2 mmol) NaH is added to a solution of 70 mg (0.173 mmol) 3-[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-4-yl]-phenol in 2 ml DMF. This mixture is stirred at room temperature for 1 h. After that 28 mg (0.207 mmol) 2-(bromoethyl)-methyl ether is added and stirring is continued for another 3 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 70 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1.[OH-].[Na+]>C(#N)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([O:12][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccc(F)c(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 3-chloro-4-hydroxybenzoate (comm, 6.48 g, 34.73 mmol) in acetonitrile was added cesium carbonate (28.29 g, 86.82 mmol) followed by 4-(bromomethyl)-1,2-difluorobenzene (comm, 10.78 g, 52.09 mmol). The reaction mixture was stirred at room temperature for 18 hours. A sodium hydroxide solution (0.5 M, 210 mL) was then added and the resulting white solid was collected by filtration to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: Cc1ccc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)cn1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: Cc1ccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(Br)cc(OC(F)(F)F)c2)cn1

Procedure:
50 mg (0.11 mmol) of the compound of Example 41A is reacted analogously to the synthesis of the compound of Example 1 with 15 mg (0.13 mmol) of 4-imidazolinone-hydrochloride. 47 mg (81% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([OH:17])[CH:14]([OH:16])[CH3:15]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:17][CH2:13][CH:14]([OH:16])[CH3:15])=[O:3]
Reactant: CC(O)CO
Reactant: COc1ccccc1OC(=O)Cl
Product: COc1ccccc1OC(=O)OCC(C)O

Procedure:
The reaction of 2-methoxyphenyl chloroformate with propylene glycol is conducted on a 0.01 mole scale employing the same conditions as described in Example III. A 0.9 g yield of the pure product is obtained as an oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10](F)=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].C([OH:23])C#CC.[K].CC(C)([O-])C>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([OH:23])=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(c2cccc(C(C)=O)c2F)CC1
Reactant: CC#CCO
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CS(C)=O
Product: CCN1CCC(c2cccc(C(C)=O)c2O)CC1

Procedure:
Preparation according to Example 5: 1-[3-(1-ethylpiperidin-4-yl)-2-fluorophenyl]ethanone (12 mg, 0.048 mmol), dimethylsulfoxide (1 ml), 2-butyn-1-ol (6.7 mg, 0.096 mmol), potassium-tertbutoxide (11 mg, 0.096 mmol). MS m/z (relative intensity, 70 eV) 247 (M+, 57), 232 (bp), 218 (28), 147 (24) 84 (67).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16](OCC)=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[S:13][N:12]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([CH2:16][OH:17])=[C:14]([C:21]([F:22])([F:23])[F:24])[S:13][N:12]=2)=[CH:9][CH:10]=1)([F:1])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(F)F)cc2)nsc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Temperature: 0 °C

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-[4-(1,1-difluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate (450 mg, 1.23 mmol, 1.00 equiv), tetrahydrofuran (4 mL). This was followed by the addition of LiAlH4 (2.5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 15 min at room temperature (20 degree). The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 5×5 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (16:84). This resulted in 110 mg (28%) of [3-[4-(1,1-difluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H10F5NOS, 324.0 (M+H). found 324.0.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[CH2:17]([N:16]1[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=[C:12]1[CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2ccccc2n1CCc1ccccc1
Product: C(#Cc1ccccn1)CCc1nc2ccccc2n1CCc1ccccc1
Yield: 25.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (46 mg, 0.22 mmol) and 2-(but-3-ynyl)-1-phenethyl-1H-benzo[d]imidazole (62 mg, 0.22 mmol). The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH: from 100/0 to 96/4 as eluent) to afford 20 mg of 1-phenethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a light brown oil (Yield: 25%).