Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])N=CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]1[CH:31]([C:32]([OH:34])=[O:33])[CH2:30][CH2:29][C:27](=O)[CH2:26]1.C(O)(=O)C.Cl>O>[C:1]([N:9]1[C:27]2[CH2:26][CH2:25][CH:31]([C:32]([OH:34])=[O:33])[CH2:30][C:29]=2[C:23]2[C:18]1=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N(N=Cc1ccccc1)c1ccccc1F
Reactant: O=C1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCc2c(c3cccc(F)c3n2C(=O)c2ccccc2)C1
Reaction time: 2 h

Procedure:
A solution of 6.4 g. benzaldehyde 1-benzoyl-1-(2-fluorophenyl)hydrazone and 5.35 g. of cyclohexanone-4-carboxylic acid in 50 ml. glacial acetic acid and 10 ml. of glacial acetic acid saturated with hydrogen chloride was heated under reflux for two hours. An additional 10 ml. glacial acetic acid saturated with hydrogen chloride was then added and heating under reflux was continued two additional hours. A further 5 ml. glacial acetic acid saturated with hydrogen chloride was added and heating under reflux was continued another two hours. The mixture was cooled, 25 ml. water was added portion-wise, and the resulting solid was collected by filtration and washed with water to yield 3.54 g. of the title compound; m.p. 250°-251°C. (acetic acid-water).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=3[N:3]=[C:2]2[O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])=[CH:13][CH:14]=1
Reactant: Oc1ccccc1F
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Br)n2Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1ccccc1F)n2Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of 8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (50 mg, 0.121 mmol, intermediate 62) in DMF (1 mL) was added 2-fluorophenol (16.4 mg, 0.146 mmol) followed by potassium carbonate (25.2 mg, 0.182 mmol). The reaction was stirred at 80° C. for 4 h. The mixture was partitioned between ethyl acetate and brine. The organic phase was washed with saturated aqueous ammonium chloride, dried and concentrated to give crude product, which was purified by preparative HPLC to give 7-(4-fluorobenzyl)-8-(2-fluorophenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (19.8 mg, 36.9% yield) as white solid. 1H-NMR (CD3OD) δ 7.52-7.56 (m, 2H), 7.43-7.45 (t, 1H), 7.2-7.38 (m, 3H), 7.08-7.13 (t, 1H), 5.51 (s, 2H), 4.09-4.13 (t, 2H), 3.60-3.63 (t, 2H), 3.37 (s, 3H), 1.86-1.90 (m, 2H). LCMS retention time 2.604; LCMS MH+ 443.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[C:28]1([SH:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](=[O:23])[S:38][C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:25])([F:27])[F:26])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: Sc1cccc2ccccc12
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Sc3cccc4ccccc34)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with naphthalene-1-thiol (88.0 mg). This gives, after chromatographic purification, S-1-naphthyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (100 mg, 37%).
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])C.Cl.[F:30][C:31]([F:39])([F:38])[C:32]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33]1.CN1CCCC1>C1COCC1.CCOC(C)=O>[F:27][C:8]1[CH:9]=[C:10]([CH3:26])[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:12][C:7]=1[NH:6][C:5]([NH:37][CH2:36][CH2:35][C:32]1([C:31]([F:39])([F:38])[F:30])[CH2:34][CH2:33]1)=[O:4]
Reactant: NCCC1(C(F)(F)F)CC1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)nc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC4(C(F)(F)F)CC4)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 41.8 %

Procedure:
Treat a mixture of prop-1-en-2-yl(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (1.09 g, 2.86 mmol) and 2-(1-(trifluoromethyl)cyclopropyl)ethanamine hydrochloride (0.542 g, 2.86 mmol) in THF (30 mL) with 1-methylpyrrolidine (1.52 mL, 14.3 mmol) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (MeOH/EtOAc). Treat the resulting material with acetonitrile, cool to −20° C. for 2 h, collect the solids via filtration, rinse with acetonittrile (−20° C.) and dry to afford the title compound as a pale yellow solid (570 mg, 42% yield). MS (m/z): 477.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[I:43][CH:44](O)[CH3:45].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:45][CH2:44][I:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)I
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)OCCI)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 55 %

Procedure:
In a manner similar to the method described in Example 1, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200 mg, 0.324 mmol) was reacted with iodoethanol (Aldrich, 220 mg, 1.28 mmol) in the presence of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 121.6 mg, 0.478 mmol), triethylamine (203 mg, 2.00 mmol) to give chiral 2-iodoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as an off-white solid (137.4 mg, 55% yield). MS (ES+) m/z calcd. for C33H33Cl2F2IN3O4: [(M+H)+]: 770. found: 770.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:17]([NH2:26])=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:16]3[CH:25]=[CH:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:17]=3[NH:26][C:2](=[O:3])[C:1]2=[O:5])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(Nc2ccc3ccccc3c2N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Temperature: 25 °C

Procedure:
To an anhydrous tetrahydrofuran (10 mL) solution of oxalyl chloride (162 μL, 1.89 mmol) was dropwise added an anhydrous tetrahydrofuran (10 mL) solution of N2-(3-methoxyphenyl)naphthalene-1,2-diamine (500 mg, 1.89 mmol) under cooling in an ice-bath. The mixture was stirred under cooling in an ice-bath for 30 minutes and at room temperature for one hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and purified by silica gel chromatography (chloroform/methanol=97/3) after removing the solvent by evaporation under reduced pressure. The obtained solid was washed with ethyl acetate/methanol (=1/1) to obtain the titled compound as a slightly beige crystal (572 mg, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([CH:19]=[O:20])=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O.O.CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:22])=[O:20])=[CH:5][CH:4]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C=O)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: 65 °C
Yield: 61.4 %

Procedure:
Intermediate 28 (1.1 gm, 0.0034 mol) in acetone (5 ml) was heated to 60-70° C. for 10 min. To the above suspension was added dropwise a hot solution of potassium permanganate (1.07 gm, 0.0068 mol) in water:acetone (1: 3) (15 ml) for 10 min. The reaction was heated to 60-70° C. for 10 min., cooled to room temperature and filtered. The residue washed with acetone and the filterate was extracted with 10% sodium hydroxide solution. Acidification, followed by filteration and washing of the precipitate yielded 4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (0.6 gm) as white solid, mp: 178° C. (dec.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][C:38]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:41]4[CH:40]=[CH:39][C:38]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:37]([O:36][CH3:35])[CH:42]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1NS(C)(=O)=O
Yield: 26.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 example 71) (150 mg, 0.38 mmol) was coupled with N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65C) (149 mg, 0.45 mmol) using sodium carbonate (121 mg, 1.14 mmol) and Pd(PPh3)2Cl2 (2 mg, 0.001 mmol) in DME/water (10/1 ml) to afford 98 mg (26.2% yield) after purification by column (Silica gel 60/120) using 65% ethyl acetate in hexane as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[CH:13](=O)[CH2:14][CH3:15]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCN2
Reactant: CCC=O
Agent: [Pd]
Solvent: CCO
Product: CCCN1CCCc2cc(OC)ccc21
Yield: 54 %

Procedure:
A solution of 148.6 g. of 6-methoxy-1,2,3,4-tetrahydroquinoline and 58 g. of propionaldehyde in 275 ml. of ethanol was hydrogenated at 60 psi over 15 g. of 15% palladium on carbon at room temperature for 2 hours and then at 50° C. overnight. The catalyst was removed by filtration and the filtrate concentrated to give a brown oil which was distilled to give 100.5 g. of 6-methoxy-1-n-propyl-1,2,3,4-tetrahydroquinoline (54% yield) as an oil boiling in the range 115°-128° C. at 0.02 Torr.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][O:13][C:12]3[C:15]4[C:20]([C:21]([OH:24])=[C:22]([CH3:23])[C:11]2=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]([F:32])([F:31])[S:27]([O-])(=[O:29])=[O:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:25][C:26]([F:32])([F:31])[S:27]([O:24][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]2[O:13][CH2:14][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:11]=2[C:22]=1[CH3:23])(=[O:29])=[O:28]
Reactant: Cc1c2c(c3ccccc3c1O)OCC2c1ccc(C(C)C)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1c2c(c3ccccc3c1OS(=O)(=O)C(F)(F)F)OCC2c1ccc(C(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ol obtained in Reference Example 252 (2.60 g, 8.17 mmol) and 4-dimethylaminopyridine (2.0 g, 16.3 mmol) in pyridine (30 mL) was added anhydrous trifluoromethanesulfonate (1.51 mL, 9.00 mmol) at room temperature at 0° C., and the mixture was stirred at 50° C. for 8 hours. Water was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1 N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 2.8 g (yield 76%) of the title compound. Oily matter.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 58 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 58% of theory, C35H43N7O5 (641.2) Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1) ##EQU88##
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29]Br)=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:29][CH2:28][O:27][C:26]3[CH:31]=[CH:32][C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:24]([N+:33]([O-:35])=[O:34])[CH:25]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2CCN(CCOc3ccc(OCc4ccccc4)c([N+](=O)[O-])c3)CC2)cc1
Yield: 82.4 %

Procedure:
From a mixture of 4-(4-methylbenzyl)piperidine (1.96 g, 30.36 mmol), 2-(4-benzyloxy-3-nitrophenoxy)ethyl bromide (1.825 g, 5.18 mmol) and KI (100 mg) in toluene (50 mL) was obtained 1.965 g (80%) of 4-(4-methylbenzyl)-1-(2-(4-benzyloxy-3-nitrophenoxy)ethyl)piperidine as yellow solid, mp. 176-7° C. 1H NMR (CDCl3) 1.25-1.39 (m, 2H), 1.46-1.54 (m, 1H), 1.60-1.66 (m, 2H), 2.00-2.07 (m, 2H), 2.320 (s, 3H), 2.500 (d, 2H, J=9), 2.754 (t, 2H, J=6), 2.93-2.97 (m, 2H), 4.068 (t, 2H, J=6), 5.179 (s, 2H), 7.02-7.10 (m, 4H), 7.33-7.46 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A round bottom flask with magnetic stirrer was charged with (2-nitro-phenyl)-acetic acid (10.0 g, 55.0 mmol) and methanol (70 mL) under an argon atmosphere. To the resulting yellow solution at room temperature was added thionyl chloride (12.1 mL, 166 mmol) dropwise via addition funnel (Note: Reaction is very exothermic). The resulting reaction mixture was stirred at room temperature for 12-18 hours and concentrated in vacuo to afford 13.3 g of crude (2-nitro-phenyl)-acetic acid methyl ester as an orange oil. This material was used directly in subsequent reactions.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:22])[C@H:13]1[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@H:14]1[OH:15]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:21][CH2:20][C@H:18]2[O:19][C@H:13]([CH2:12][O:22][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C@@H:14]([OH:15])[C@@H:16]2[OH:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.33 g (27.945 mmol) of p-toluenesulphonyl chloride were added at 0° C. to a solution of 2.16 g (13.15 mmol) of 2,5-anhydro-D-mannitol in 88 ml of pyridine. The mixture was heated to room temperature and stirred for a further 24 hours. The reaction was hydrolysed using ice-water and extracted using CH2Cl2, and the combined organic phases were washed with 3N HCl and NaCl. After drying over MgSO4, the solvent was subsequently removed under reduced pressure. The crude product was purified by means of column chromatography (hexane/ethyl acetate 1:2). Yield: 3.00 g (48% of theory).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Br:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([S:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: Clc1ccnc2ncccc12
Product: Oc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol (120 mg, 0.30 mmol) for 40 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (87 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.15 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 6.66 (d, J=8.83 Hz, 2H) 7.08-7.47 (m, 6H) 7.56 (d, J=7.72 Hz, 1H) 7.65 (m, 1H) 7.92 (dd, J=4.41 Hz, J=8.46 Hz, 1H) 8.18 (d, J=6.99 Hz, 1H) 9.14 (dd, J=8.83 Hz, 1H) 9.17 (dd, J=5.88 Hz, J=1.84 Hz, 1H) 9.80 (s, 1H) 11.16 (br s, 1H) 14.53 (br s, 1H); MS (ESI+) m/z 529, 531 (M+H−TFA)=; (ESI−) m/z 528, 530 (M−H−TFA)−.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])(=O)=O.[Br:16][C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26](O)([CH3:28])[CH3:27])=[N:25][C:20]2=[N:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:16][C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([CH3:28])([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:27])=[N:25][C:20]2=[N:19][CH:18]=1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylsilyl trifluoromethanesulfonate (4.85 ml, 21.5 mmol) was added dropwise over 15 min to a cooled (−50° C.) solution of 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (5.0 g, 19.5 mmol) and diisopropylethylamine (4.76 ml, 27.5 mmol) in dichloromethane (150 ml). The mixture was stirred for 20 min then allowed to warm to ambient temperature overnight. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 1N hydrochloric acid (100 ml) and water (100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. The red oil was purified by dry flash column chromatography on silica eluting with dichloromethane on a gradient of methanol (0-3%). Collecting the appropriate fractions gave 3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine as a pale yellow oil which crystallised on standing (6.21 g, 86%): δH (400 MHz, CDCl3) 0.64 (6H, q, J 8), 0.97 (9H, t, J 8), 7.50 (1H, d, J 7), 7.72 (1H, s), 8.35 (1H, d, J 7).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])[CH:2]=1.C(O)C.[OH-].[K+].Cl>O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])[CH:2]=1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)Sc1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
the mixture of 26 mg of ethyl 2-(10,11-dihydro dibenzo[b,f]thiepin-3-yl)-propionate, 1 ml of ethanol, 200 mg of potassium hydroxide and 1 ml of water was stirred at room temperature for 1 hour. The solvent was distilled off to obtain the residue, which was acidified with hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 24 ml of 2-(10,11-dihydro dibenzo[b,f]thiepin-3-yl)-propionic acid as pale yellow oil.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[F:5][C:6]([F:17])([F:16])[O:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15].N1C=CC=CC=1>C(Cl)Cl>[O:15]=[C:11]1[N:10]([CH2:9][CH2:8][O:7][C:6]([F:17])([F:5])[F:16])[CH2:14][CH2:13][N:12]1[C:1]([Cl:4])=[O:2]
Reactant: O=C1NCCN1CCOC(F)(F)F
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCN(CCOC(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20 wt % in toluene, 0.497 mL, 0.945 mmol) in DCM (4 mL) was treated slowly with a solution of 1-(2-(trifluoromethoxy)ethyl)imidazolidin-2-one (0.156 g, 0.787 mmol) and pyridine (0.127 mL, 1.575 mmol) in DCM (4 mL), stirred for 1 h at 0° C., then concentrated to dryness to afford 2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carbonyl chloride (100% yield assumed). MS [quenched in MeOH] (ESI) m/z: 257.1 (M+H+).