Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[N:26][C:25]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O.[C:48]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C@:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:21][CH3:48])[CH3:2]
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(C)s3)oc2C)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@](CC)(Cc1ccc(OCCc2nc(-c3ccc(C)s3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
(S)-3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (255 mg, 0.85 mmol), toluene-4-sulfonic acid 2-[5-methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]ethyl ester (383 mg, 1.02 mmol) and Cs2CO3 (335 mg, 1.02 mmol) are combined in anhydrous DMF (6 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (50 mL), and washed with water then brine. The organic layer was dried with MgSO4 and concentrated in vacuo to a viscous tan oil. The residue was purified by flash column chromatography (200 g silica, hexanes to 25% EtOAc/hexanes) to provide the title compound as a colorless oil (201 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=3.4 Hz, 1H), 7.22-7.13 (m, 4H), 6.97 (t, J=7.2 Hz, 1H), 6.85-6.80 (m, 4H), 6.72 (dd, J=3.6, 1.2 Hz, 1H), 4.23-4.17 (m, 4H), 3.26 (A of Abq, J=13.6 Hz, 1H), 3.11 (B of Abq, J=13.6 Hz, 1H), 2.94 (t, J=5.6 Hz, 2H), 2.50 (s, 3H), 2.34 (s, 3H), 1.39 (s, 3H), 1.22 (t, J=7.2 Hz, 3H); MS (EI+) 505.9 (M+H); 637.8 (M+H+Cs).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[N:7]1[O:8][N:9]=[C:5]2[CH:4]=[C:3]([CH2:2][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]4([C:40]5[C:31](=[CH:32][C:33]6[O:38][CH2:37][CH2:36][O:35][C:34]=6[CH:39]=5)[O:30][CH2:29]4)[C:21]3=[O:41])[CH:11]=[CH:10][C:6]=12
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccc2nonc2c1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc3nonc3c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(bromomethyl)-2,1,3-benzooxadiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ7.86 (d, J=9.3 Hz, 1H), 7.75 (s, 1H), 7.43-7.37 (m, 1H), 7.25-7.19 (m, 2H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.23 (s, 1H), 5.13 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.94 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.24-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 149.0, 148.7, 144.8, 141.4, 139.7, 138.4, 132.0, 131.4, 129.0, 124.3, 124.0, 120.6, 117.8, 113.9, 111.4, 108.8, 99.6, 80.1, 64.5, 63.9, 58.0, 44.0; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][CH:12]1[CH:17]([O:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH:14]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:11][CH:12]1[CH:17]([O:18][CH2:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:16][CH2:15][CH:14]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(OCC(O)c2ccccc2)C(F)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(OCC(=O)c2ccccc2)C(F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
A solution of oxalyl chloride (0.054 mL, 0.623 mmol) in dichloromethane (10 mL) was cooled to −78° C. Dimethylsulfoxide (0.088 mL, 1.36 mmol) was added dropwise and the reaction mixture was stirred for 5 min. (−) tert-Butyl 3-fluoro-4-(2-hydroxy-2-phenylethoxy)cyclohexylcarbamate (200 mg, 0.567 mmol) was then added as a solution in dichloromethane (1 mL). After 5 min of stirring, diisopropylethylamine (0.494 mL, 2.84 mmol) was added in one portion, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was then poured saturated sodium bicarbonate, the layers were separated and the aqueous extracted (4×) with dichloromethane. The combined organic layers were dried with anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (hexane: ethyl acetate) gave tert-Butyl 3-fluoro-4-(2-oxo-2-phenylethoxy)cyclohexylcarbamate (175 mg, 88% yield) as a white solid.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CS(C)=[O:19]>O>[O:19]=[C:3]1[CH:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2]1
Reactant: CS(C)=O
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: O
Product: O=C(O)CCCC1C(=O)Nc2ccccc21
Yield: 96 %

Procedure:
Concentrated HCl (16.6 mL) was added dropwise with stirring, over 10 minutes, to a solution of 4-(3-indolyl)butanoic acid [II: R1 =R3 =H, R2 =(CH2)3COOH] (2.00 g) in DMSO (7.0 mL) at room temperature (method of Savige WE, Fontana A, J. Chem. Soc. Chem. Commun. 1976:599). After 15 minutes reaction, the mixture was diluted with water (80 mL) and extracted with EtOAc (4×100 mL). Removal of the solvent gave crude 4-(2-oxo-3-indolinyl)butanoic acid [III: R1 =R3 =H, R2 =(CH2)3COOH] (2.07 g, 96%) as a green-brown solid; mp (water) 169°-171° C. (Hinman RL, Bauman CP, J. Org. Chem, 1964;29:1206 record mp 170°-171° C.).
Reaction SMILES: [N:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29]Br.O>CN(C=O)C>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2][CH2:3]1
Reactant: Fc1cccc(F)c1CBr
Reactant: NC(=O)c1ccc2nc(N3CCNCC3)[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)c1ccc2nc(N3CCN(Cc4c(F)cccc4F)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
Piperazinyl-benzimidazole-5-carboxamide (0.186 g, 0.5 mMol) was taken in 5 mL DMF and 0.101 g (1 mMol) triethylamine was added and stirred for 15 minutes at room temperature. To this reaction mixture was added 0.104 g 2,6-difluorobenzyl bromide and the mixture was stirred for 20 h. This was poured into water and extracted with methylene chloride (3×50 mL). The combined extract was further washed with brine, water and dried over MgSO4. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with chloroform-methanol (0 to 5% methanol, gradient). Evaporation of the desired fraction gave 48.9 mg of the desired product; MS(ESI) m/e 356 (M+).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=[S:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:15][S:3][C:1](=[N:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=S)NC(=O)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CSC(C)=NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A mixture of N-(thioacetyl)-2,4-dichlorobenzamide (400 mg, 1.6 mmol) and K2CO3 (445 mg, 3.22 mmol) in anhydrous acetonitrile (20 mL) was stirred at ambient temperature. Iodomethane (458 mg, 0.2 mL, 3.22 mmol) was added and the reaction mixture was then stirred for 2.5 h. Solvent was removed in vacuo and the residue was partitioned between ether and water. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil (406 mg): NMR (CDCl3,300 MHz): δ 7.86 (d, 1H, J=8), 7.47 (d, 1H, J=2), 7.32 (dd, 1H, J=8, 2), 2.40 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](N3CCC(CC(O)=O)CC3)=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([O:44][CH2:45]Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].[I-].[K+].[C:49](=[O:52])(O)[O-:50].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]([CH:21]3[CH2:22][CH:23]([CH2:26][C:49]([O:50][CH2:45][O:44][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[O:52])[CH2:24][CH2:25][NH:20]3)=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)C(=O)OCCl
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(N2CCC(C(=O)N3CCC(CC(=O)O)CC3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)CC1CCNC(C(=O)C2CCN(c3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)CC2)C1

Procedure:
A suspension of 1 equivalent of 1-[4-(N-benzyloxycarbonylamidino)-phenyl]-4-[4-(carboxymethyl)-piperidinocarbonyl]-piperidine is stirred for 2 days with 2 equivalents each of chloromethyl pivalate, potassium iodide, potassium bicarbonate and potassium carbonate in dimethylformamide at ambient temperature for 2 days. After pouring into water, extraction with ethyl acetate and evaporation down of the ethyl acetate extract, the desired product is obtained which is then chromotagraphed over silica gel. The following compounds are obtained analogously to Example 10:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([NH:21][C:22]([N:11]2[C:12]3[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1000 %

Procedure:
Sodium hydride (802 mg, 20.0 mmol, 60% in oil) was suspended in N,N-dimethylformamide (40 ml); 5-nitroindole (2.50 g, 15.4 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 30 minutes. Phenyl isocyanate (2.01 ml, 1.23 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 1.5 hours. Water (80 ml) was added to the reaction mixture; the reaction mixture was stirred at room temperature for 30 minutes; and the precipitated crystals were filtered off, washed by water and diethyl ether one by one, and dried by means F of suction to yield the title compound (3.53 g, 12.3 mmol, 79.8%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2>O1CCCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Solvent: C1CCOC1
Product: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-trifluoromethyl-1H-indole-5-carbonitrile (Intermediate 33, 0.16 g, 0.761 mmol) in tetrahydrofuran (5 mL) cooled in an ice-water bath, was treated with a 1M solution of borane tetrahydrofuran complex (3.05 mL, 3.05 mmol) dropwise via syringe. The reaction mixture was then left to stir under argon for 18 hrs while allowing it to warm to room temperature. The reaction mixture was then quenched with methanol (10 mL) and stirred at room temperature for 10 min. The reaction mixture was then poured onto a SCX cartridge (10 g) and washed well with methanol. The desired product was then eluted using 2M ammonia/methanol solution. Evaporation to dryness gave the title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([CH3:25])[CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=O)[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:59]([CH2:61][NH2:62])[OH:60]>CN(C=O)C>[F:1][CH:2]([CH3:25])[CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([NH:62][CH2:61][CH2:59][OH:60])=[O:24])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OCC(C)F)c12
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCO)sc2ncnc(Nc3cccnc3OCC(C)F)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-(2-Fluoropropoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (36.2 mg), HATU (42 mg) and Hünig's base (34 μl) were dissolved in DMF (2 ml) and ethanolamine (9 μl) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was purified directly by chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C)c2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[5-methyl-3-(3-methylphenylsulfonyloxy)phenoxy]propanol (505 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.6 mL, 4.7 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (450 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.69 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 6.61 (s, 1H), 6.44 (s, 1H), 6.35 (s, 1H), 4.18 (t, J=6.0 Hz, 2H), 2.85 (t, J=6.1 Hz, 2H), 2.43 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.P(=O)(O)(O)O>C(O)(=O)C>[C:26]1([C:8]2[C:9]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:10]=3[NH:11][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)cc2s1
Reactant: O=C1CCCCC1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3=CCCCC3)c2s1
Temperature: 80 °C
Yield: 69 %

Procedure:
A solution (0.2 M) of methyl 5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in acetic acid was treated with acetic anhydride (10 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. for 3 h, then was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was purified by flash chromatography on silica gel (1:4 AcOEt/petroleum ether) affording the title compound (69%) as a solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)#[N:4].ClCO[CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].O.CN(C)[CH:23]=[O:24]>C(Cl)(Cl)Cl>[C:3]([CH2:5][C:6]1[NH:7][C:8]([CH2:23][O:24][CH:15]([Si:16]([CH3:17])([CH3:18])[CH3:19])[CH3:14])=[N:9][CH:10]=1)#[N:4]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#CCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(OCc1ncc(CC#N)[nH]1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
373 mg of sodium hydride (60%) was added to 5 ml of dimethylformamide, and a solution of 1.0 g of 4-cyanomethylimidazole in 10 ml of dimethylformamide was added dropwise to the resulting suspension. After 1 hour of stirring at room temperature, to the solution was added 1.9 ml of (2-chloromethoxyethyl)trimethylsilane and stirred at room temperature for 2 hours. The reaction solution was mixed with water and chloroform, and the resulting organic layer was collected and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to silica gel column chromatography eluted with hexane-ethyl acetate (1:1) to obtain 1.128 g of 4-cyanomethyl-1-trimethylsilylethoxymethylimidazole and 0.362 g of 5-cyanomethyl-1-trimethylsilylethoxymethylimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:3]=1[Cl:18]>C(O)(=O)C.[Zn]>[Cl:18][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cc2cccc(Cl)c2Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Cc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
1,2-Dichloro-3-(4-nitrobenzyl)benzene (25.0 g, 88.6 mmol) obtained in Step 1 was dissolved in acetic acid (400 ml), zinc powder (70 g, 1.1 mol) was added by portions at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite and washed with ethanol. The filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration on the way. The filtrated solid was washed with diethyl ether, and dissolved in ethyl acetate (500 ml) and water (500 ml), 4N aqueous sodium hydroxide solution was added to neutralize the aqueous layer. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration on the way. The filtrated solid was washed with n-hexane and vacuum dried to give the object product (18.1 g, yield 81%) as a pale-brown solid.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:37])=[C:23]([CH:36]=1)[C:24]([NH:26][C:27]1[N:32]=[CH:31][C:30]([C:33](Cl)=[O:34])=[CH:29][CH:28]=1)=[O:25]>ClCCl.O>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:33]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24](=[O:25])[C:23]4[CH:36]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=4[CH3:37])=[N:32][CH:31]=3)=[O:34])[C:4]=2[CH:3]=[CH:2]1
Reactant: c1cc2c(s1)CCCCN2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a cooled (0° C.) mixture of 0.306 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 1.11 μl of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride and the mixture is stirred overnight at room temperature under argon. The mixture is diluted with 50 ml of dichloromethane and 20 ml of water and the organic layer separated. The organic layer is washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated, concentrated to dryness under vacuum to give a glass. Crystallization from ethyl acetate-hexane gives 0.35 g of white crystals, m.p. 178°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([N:8]([C:15](=[O:19])[C:16](Cl)=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:30][O:31][CH2:32][CH2:33][OH:34].CCN(CC)CC>C1COCC1>[CH3:30][O:31][CH2:32][CH2:33][O:34][C:16](=[O:17])[C:15]([N:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:19]
Reactant: O=C(Cl)C(=O)N(c1ccccc1)c1cc(F)ccc1C(=O)CCc1ccccc1
Reactant: COCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOC(=O)C(=O)N(c1ccccc1)c1cc(F)ccc1C(=O)CCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of {[5-fluoro-2-(3-phenyl-propionyl)-phenyl]-phenyl-amino}-oxo-acetyl chloride (540 mg) in THF (3 mL) was added 2-methoxyethanol (0.12 mL), followed by Et3N (0.22 mL). The reaction mixture became a pale yellow slurry: additional THF (2 mL) was added, and the mixture allowed to stand for 1 h. The mixture was then quenched with NH4Cl (sat'd aq), extracted with EtOAc, washed with brine, and concentrated to yield N-[5-fluoro-2-(3-phenyl-propionyl)-phenyl]-N-phenyl-oxalamic acid 2-methoxy-ethyl ester (504 mg) as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][NH:18][CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:37]1([CH3:46])[C:38]([C:43](Cl)=[O:44])=[CH:39][CH:40]=[CH:41][CH:42]=1>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][N:18]([C:43]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[CH3:46])=[O:44])[CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNC4)nc12
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccccc3C)C4)nc12
Yield: 50 %

Procedure:
To a suspension of 0.01 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride in 0.8 ml tetrahydrofurane were added at 0–4° C. 0.02 ml N-ethyldiisopropylamine and 0.004 ml o-toluoyl chloride. The mixture was refluxed over night, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate/methanol 98:2 to yield 0.006 g (50%)[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-o-tolyl-methanone as yellow solid; MS (ISP): m/e=490 (M+H+).