Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([CH3:8])[CH:5]([OH:7])O.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O:29]CC>C1COCC1>[Si:9]([O:29][CH2:8][CH:4]([F:3])[CH2:5][OH:7])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(F)C(O)O
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC(F)CO)(c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a flask filled with THF (20 mL) was added sodium hydride (0.255 mg, 10.62 mmol) followed by the addition of 2-fluoropropanediol (1.0 g, 10.62 mmol) in THF. The reaction was stirred for 45 minutes followed by the addition of tert-butyldiphenylsilylchloride (2.92 g, 10.628 mmol) and stirred vigorously for another 45 min as the reaction gradually approaches room temperature. The reaction mixture was poured into a separatory funnel filled ⅓ of the way with ether and extracted with 15% K2CO3, washed with brine and dried over sodium sulfate. The resulting clear oil was purified by column chromatography (SiO2; 0%->30% EtOAc:Hx to provide the title compound as a clear oil. 1H NMR (500 MHz, CDCl3) δ 1.56 (s, 9H), 3.83-3.93 (m, 4H), 4.58-4.69 (d, J=52 Hz, 1H), 7.39-7.47 (m, 6H), 7.72-7.73 (m, 4H) ppm. HRMS [M+H] C19H25FO2Si calc'd 333.1681, found 333.1667.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:24]=4)[O:20][C:19]3=[O:40])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N1C2C(=CC=CC=2)C(C2C=C(C3C4C(=CC=CC=4)N(CC)C=3C)OC2=O)=C1C)C.[CH3:71][O:72][C:73]1[CH:74]=[C:75]2[C:79](=[CH:80][C:81]=1[O:82][CH3:83])[NH:78][CH:77]=[CH:76]2.C(N1C2C(=CC=CC=2)C=C1C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[C:19](=[O:40])[O:20][C:21]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:24]=4)([C:76]4[C:75]5[C:79](=[CH:80][C:81]([O:82][CH3:83])=[C:73]([O:72][CH3:71])[CH:74]=5)[NH:78][CH:77]=4)[CH:22]=3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2cc[nH]c2cc1OC
Reactant: O=C1OC(c2cn(Cc3ccccc3)c3cc(F)ccc23)=CC1c1cn(Cc2ccccc2)c2cc(F)ccc12
Agent: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Agent: CCn1c(C)cc2ccccc21
Product: COc1cc2[nH]cc(C3(c4cn(Cc5ccccc5)c5cc(F)ccc45)C=C(c4cn(Cc5ccccc5)c5cc(F)ccc45)C(=O)O3)c2cc1OC

Procedure:
When 3,5-bis(6-fluoro-1-benzyl-3-indolyl)-2(3H)-furanone is substituted for 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone and 5,6-dimethoxyindole is substituted for 1-ethyl-2-methylindole in the procedure described in part C of this example, there is obtained 3,5-bis(6-fluoro-1-benzyl-3-indolyl)-5-(5,6-dimethoxy-3-indolyl)-2(5H)-furanone (Formula III: R=C6H5CH2 ; R1 =R2 =R3 =H; Y=6-F; Y1 =5,6-(CH3O)2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([OH:15])(=[O:14])[CH2:10]C(O)=O.C([O-])(=O)C.[NH4+:20]>C(O)C>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH:7]([NH2:20])[CH2:10][C:9]([OH:15])=[O:14])[CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cccnc1
Temperature: 38 °C
Yield: 65.2 %

Procedure:
The reaction flask was charged with 300 g (264.3 mL)(2.8 mol) of cold 3-pyridine carboxaldehyde and 60 mL of absolute ethanol. A reaction temperature of 13° C. resulted. With good stirring, 291.36 g (2.8 mol) malonic acid was added in one portion (solid addition) over about 2 min, followed by 90 mL ethanol. Immediately following this addition, 323.73 g (4.2 mol) ammonium acetate was added over about 10 min (solid addition), followed by 250 mL ethanol. During this addition, the reaction cooled to about 38° C. The bright orange mixture was heated to and maintained under gentle reflux for 5 h. The heating mantle was removed, and the mixture was allowed to cool to ambient temperature overnight. The solid was collected by suction filtration (50 min) and washed with 400 mL methanol (30 min). The filtercake was washed with a second portion of 200 mL methanol (10 min). The filtercake was partially dried under suction for about 60 min. The solids were dried in vacuo at 35-40° C. to constant weight (38 h) to yield 303.38 g (65.2%) 3-amino-3-(3′-pyridyl)propionic acid as a white powder.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH2:19][CH2:20][C:21]#N)[CH3:18])[N:4]=1.[NH3:23]>C(Cl)Cl.[Ni]>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH3:18])[CH2:19][CH:20]([NH2:23])[CH3:21])[N:4]=1
Reactant: COc1cc2nc(N(C)CCC#N)nc(N)c2cc1OC
Reactant: N
Agent: [Ni]
Agent: Cl
Solvent: ClCCl
Product: COc1cc2nc(N(C)CC(C)N)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25 gms, 0.77 moles of N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride, 25 gms of Raney-Nickel and 500 ml of 9.8% methanolic ammonia solution were charged in an autoclave. The reaction mixture was hydrogenated at 70° C. under a pressure of 5 kg/cm2 (70 psi) for 2 hours. The reaction mass was cooled to room temperature, filtered on hyflo bed and washed with 200 ml methanol. The solvent was distilled under reduced pressure. The residue obtained was stirred in 50 ml methylene chloride and concentrated under reduced pressure at 40° C. The residue was dissolved in 200 ml isopropanol and acidified to pH 1-2 with isopropanolic HCl. The N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl propylenediamine hydrochloride obtained was isolated by filtration and dried under suction.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8]C[CH2:10][C:5]2=[N:4][CH:3]=1.[I:11]N1C(=O)CCC1=O.[C:19](O)(=O)[CH3:20]>>[CH2:7]([N:6]1[C:2]([CH3:1])=[C:3]([I:11])[N:4]=[C:5]1[CH2:10][CH2:19][CH3:20])[CH3:8]
Reactant: CC(=O)O
Reactant: Cc1cnc2n1CCCC2
Reactant: O=C1CCC(=O)N1I
Product: CCCc1nc(I)c(C)n1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of 3-methyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine (Eur. J. Med. Chem. 10(5), 528, 1975; 1.85 g, 13.6 mmol) in acetic acid (50 mL) was added N-iodsuccinimide (4.28 g, 19.0 mmol) and the reaction mixture was stirred for 3 h at ambient temperature. It was concentrated and the residue extracted with aqueous sodium carbonate (sat.) and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 93:7) afforded the title compound (3.00 g, 84%) as a dark brown solid. MS: m/e=262.0 [M]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=1[Cl:20])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCCCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCCCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5 g (19.0 mmol) of methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate from Example 26 in 10 ml DMF is added 3.0 g (22.8 mmol) of N-chlorosuccinimide in a single portion at room temperature. The resulting solution is allowed to stir 24 hours at room temperature. The reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered, concentrated and subjected to flash chromatography (20% EtOAc/hexanes) to yield methyl 6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate. This is used in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47].C(N(CC)CC)C>ClCCl>[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH:47][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)CCN
Reactant: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26, 1.0 eq.), 1-hydrobenzotriazole hydrate (1.2 eq.), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 eq.), beta-alanine methyl ester hydrochloride (1.1 eq.), and triethylamine (1.3 eq.) were combined in anhydrous dichloromethane in a similar manner as described in the experimental for intermediate 27 to provide (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester which was resolved via chiral chromatography to provide the title compound. Preparative chiral SFC: (Chiralpak AD-H column, 21 mm×25 cm, 40% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier, 65.0 mL/min flow rate, 2.71 retention time); 1H NMR (400 MHz, CDCl3) δ 7.63-7.69 (m, 2H), 7.58 (t, J=3.9 Hz, 2H), 7.45-7.51 (m, 3H), 7.41 (ddd, J=8.4, 7.0, 1.6 Hz, 1H), 7.14 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 6.72 (t, J=6.0 Hz, 1H), 5.31 (dd, J=9.7, 6.7 Hz, 1H), 4.75 (d, J=6.8 Hz, 1H), 3.69 (q, J=6.2 Hz, 5H), 2.55-2.71 (m, 3H), 2.28 (d, J=0.8 Hz, 3H), 1.95 (ddd, J=11.2, 8.0, 3.0 Hz, 1H), 1.78 (dd, J=11.1, 9.0 Hz, 1H), 1.64-1.72 (m, 2H), 1.15 (s, 3H), 1.08 (s, 3H); MS (M+1): 460.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:15][CH:16]=O.C(=O)([O-])O.[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[S:13][CH:15]=[CH:16][N:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CCCl
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cc2nccs2)cc1

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (0.80 g), chloroacetaldehyde (40% aqueous solution, 2.88 g) and ethanol (20 mL) was heated under reflux for 15 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 2-(4-nitrobenzyl)-1,3-thiazole was obtained as an orange oil (0.35 g, yield 39%) from a fraction eluted with hexane-ethyl acetate (9:1-2:1, v/v).
Reaction SMILES: [C:1]([O:4][C:5]([C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:6])(=[O:3])[CH3:2].[H][H].C(OC(/C=C\C1C=CC=CC=1)C)(=O)C>C1COCC1.F[B-](F)(F)F.C1([Rh+]C2CCCCC=CC=2)CCCCC=CC=1>[C:1]([O:4][CH:5]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C#Cc1ccccc1)OC(C)=O
Agent: C1=CCCCCC([Rh+]C2=CC=CCCCC2)=C1
Agent: CC(=O)OC(C)/C=C\c1ccccc1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(=O)OC(C)CCc1ccccc1

Procedure:
This reaction was performed as in Example 1 with bis(cyclooctadienyl)rhodium tetrafluoroborate (10 mg; 0.025 mmol; 0.02 equiv), R,R-1,2-bis(2,5-dimethylphospholano)benzene (6, R"=CH3 ; 9 mg; 0.03 mmol; 0.024 equiv) and 4-phenylbut-1-en-3-yn-2-yl acetate (3b; 233 mg; 1.25 mmol) in 10 mL of degassed THF until hydrogen uptake ceased to afford 0.25 g of crude product. 1H NMR analysis indicated Z-4-phenyl-3-buten-2-yl acetate (5b) as the sole product, and reduction of the olefin to afford 4-phenyl-2-butyl acetate followed by chiral GC analysis and comparison to the racemate and authentic R-4-phenyl-2-butyl acetate indicated 97.8% ee for R-Z-4-phenyl-3-buten-2-yl acetate. Further investigation indicated a bimodal reduction, with 4-phenylbut-1-en-3-yn-2-yl acetate initially chemoselectively and enantioselectively reduced to 4-phenylbut-3-yn-2-yl acetate (4b), which was then more slowly reduced to Z-4-phenyl-3-buten-2-yl acetate (5b).
Reaction SMILES: [C@@H:1]1([NH2:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:6].[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>ClCCl.C(N(CC)CC)C>[C:8]([O:12][C:13]([NH:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@@H:1]1[NH2:7])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: N[C@@H]1CCC[C@@H]1N
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
cis-1,2-Cyclopentanediamine (WO98/30574) (692 mg) was dissolved in dichloromethane (10 ml), to which triethylamine (1.1 ml) and 2-(tert-butoxycarbonyloxy-imino)-2-phenylacetonitrile (493 mg) were added, and the mixture was stirred at 0° C. for 1 hour. Thereafter, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) were additionally added, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=9:1) to obtain the title compound (395 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:32])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)=O
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(C)=O

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (2.15 g, 6.95 mmol) by reaction with m-CPBA (1.71 g, 7.64 mmol) to provide 5-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one followed by reaction with p-toluenesulfonyl chloride (1.46 g, 7.64 mmol) and ammonium hydroxide solution (10 mL) to provide 5-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one as an off-white solid, mp 173-176° C.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClCC(OC(=O)CCl)=O.[NH:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>ClC(Cl)C>[C:1]([C:20]1[NH:19][CH:23]=[CH:22][CH:21]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)O
Reactant: c1cc[nH]c1
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: CCCCCCC(=O)c1ccc[nH]1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 64 %

Procedure:
In 50 ml of dichloroethane were dissolved 6.51 g (0.05 mole) of heptanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 4.36 g (0.065 mole) of pyrrole and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 5.5 hours. After completion of .the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5.74 g of 2-heptanoyl-pyrrole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:12]([N:19]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]([CH2:32][CH3:33])[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=C(N=C=O)C=1.C(OC(CN1C2C=CC=CC=2CCCNCC1=O)=O)(C)(C)C>>[CH2:12]([N:19]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]([CH2:32][CH3:33])[CH2:24][CH2:23][N:22]([C:10](=[O:11])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:21][C:20]1=[O:34])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCC1CCNCC(=O)N(Cc2ccccc2)c2ccccc21
Agent: CC(C)(C)OC(=O)CN1C(=O)CNCCCc2ccccc21
Agent: Cc1cccc(N=C=O)c1
Product: CCC1CCN(C(=O)Nc2ccc(Cl)c(Cl)c2)CC(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
The compound was prepared by a similar method to that used in the preparation of example 49 except that 3,4-dichlorophenylisocyanate and 1-benzyl-7-ethyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine were used in place of m-tolylisocyanate and 1-tert-butyloxycarbonylmethyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine respectively in step j.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([CH2:19][NH:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][N:37]=[C:38]=[O:39]>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:15][C:16]2([CH2:17][N:18]([C:38](=[O:39])[NH:37][CH2:36][C:30]3[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=3[Cl:28])[CH2:19]2)[CH2:20]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CN(C(=O)NCc3ccc(Cl)cc3Cl)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate (200 mg, 1.01 mmol) in dichloromethane (10 mL) was added triethylamine (141 μl, 1.01 mmol) followed by 2,4-dichloro-1-(isocyanatomethyl)benzene (204 mg, 1.01 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; methanol:dichloromethane 0:1 to 1:9) to give the title compound (344 mg, 85%) as a white solid. MS (EI) m/e: 400.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][CH2:19][CH2:18][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][CH:26]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCSc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCSc2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (10 mL) at 0° C. The mixture was stirred for 30 min at 50° C., cooled to room temperature and 1-bromo-3-(4-benzyloxy-phenylsulfanyl)-propane (CAB02037, 1.686 g, 5.0 mmol) was added. The reaction mixture was stirred for 15 h and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography (eluent: ethyl acetate, Rf: 0.41). Yield: 1.724 g (78%) colourless oil. The oil was crystallised from a small amount of methanol. Yield: 1.517 g (68%). 1H-NMR (400 MHz, CDCl3) δ=1.84 (tt, J=6.4, 6.4 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 5.06 (s, 2H, —OCH2Ph), 6.52 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.33-7.44 (m, 5H), 7.52 (d, J=9.0 Hz, 2H), 8.26 (s, 2H). LRMS (FAB+): 442.2 (100, [M+H]+)
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O-:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+].Cl[CH2:26][CH:27]([OH:30])[CH2:28][OH:29].[I-].[K+].O>COCCOCCOC>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)[O-])cc2[nH]1
Reactant: OCC(O)CCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OCC(O)CO)cc2[nH]1
Yield: 26 %

Procedure:
A mixture of sodium 2-(n-undecyl)indole-6-carboxylate (5.0 g) and 3-chloro-1,2-propanediol (1.64 g) in diglyme (50 ml) was refluxed for 30 minutes. Potassium iodide (2.5 g) was added and the mixture refluxed for 48 hours. The mixture was cooled, water (50 ml) was added and the resulting emulsion was extracted with dichloromethane (2×100 ml). The combined extracts were dried over anhydrous magnesium sulphate, filtered, and the solvent evaporated to dryness. The solid residue was recrystallised from cyclohexane, filtered off and dried to give (RS)-2,3-dihydroxyprop-1-yl 2-(n-undecyl)indole-6-carboxylate (1.5 g) in the form of a white solid, m.p. 110°-112° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Methyl 4-nitrophenoxyacetate (5.0 g; 24 mmol) was dissolved in 150 ml of methanol in a reactor, followed by the addition of 480 mg of 5% Pd/C. The reactor was purged with nitrogen gas. Under a hydrogen gas atmosphere, the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reactor was purged again with nitrogen gas. The Pd/C was filtered off and the solvent was then distilled out under reduced pressure, whereby 4.1 g of a brown oil were obtained (yield: 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5](O)[C:6]([CH3:9])([CH3:8])[CH3:7])[C@H:3]1[C:11]([OH:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C@H:3]2[C@@H:4]1[C@H:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[O:12][C:11]2=[O:13]
Reactant: CC(C)(C)C(O)[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[C@@H]1OC(=O)[C@@H]2[C@H]1C2(C)C
Reaction time: 0.25 h

Procedure:
A solution of 5 g of the product of Step A in 50 ml of benzene was heated to reflux and 20 mg of p-toluene sulfonic acid were added thereto and reflux was continued for 15 minutes. The mixture was cooled and was washed with aqueous sodium hydroxide and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 benzene-ethyl acetate mixture to obtain (1R,4R,5S) 6,6-dimethyl-4-(2-methyl-prop-2-yl)-3-oxa-bicyclo (3,1,0) hexan-2-one melting at 113° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.Cl>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(O)cc2)cc1
Yield: 46.3 %

Procedure:
Hydroquinone (18 g, 163.5 mmol), 4-fluorobenzonitrile (10 g, 81.75 mmol) and potassium carbonate (23 g, 163.5 mmol) were heated to 150° C. in dimethylformamide (40 mL) for 6 hours. The cooled mixture was diluted with water and 1 N hydrochloric acid and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed yielding 8 g of the title compound. MS (m/z, APCI): 210 [M−H]−.