Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[CH2:16][CH:15]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2CC3C(=CC=CC=3)C2=O)C=CC=CC=1>>[CH2:1]([N:8]1[C:12]([CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=Cc1cncn1Cc1ccccc1)C(c1ccccc1)C2
Agent: O=C1c2ccccc2CC1c1ccccc1
Product: C(=C1c2ccccc2CC1c1ccccc1)c1cncn1Cc1ccccc1

Procedure:
1-Benzyl-5-(2-phenylindan-1-ylidenemethyl)-1H-imidazole was prepared as 1-benzyl-5-(6-methoxy-2-phenylindan-1-ylidenemethyl)-1H-imidazole above except that 2-phen-ylindan-1-one was used as a starting material. In this case after evaporation of the filtrate the residue was dissolved in diluted hydrochloric acid. The product was extracted into dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate and evaporated under reduced pressure. The crude product as its hydrochloride salt was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[S:9][CH3:10].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3]([S:9][CH3:10])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: CSc1nccc(=O)n1C
Solvent: ClC(Cl)Cl
Product: CSc1ncc(Br)c(=O)n1C
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
3-Methyl-2-methylthio-3H-pyrimidin-4-one (Step 2, 3.31 g, 21.2 mmol) was dissolved in CHCl3 (50 mL) and cooled to 0° C. under Ar. Br2 (1.25 mL, 25.4 mmol) was added via syringe, and the reaction was stirred at 0° C. for 35 min, at which time TLC analysis indicated complete consumption of starting material. The reaction was quenched with 40 mL saturated NaHCO3, warmed to RT, and stirred overnight. The reaction was extracted with CH2Cl2 (3×25 mL), and the organic extracts were combined, dried over Na2SO4, filtered, and concentrated to give the title compound, which did not require further purification. MS (ESI pos. ion) m/z: 236. Calc'd for C6H7BrN2OS: 233.95.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:10][N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[S:29][CH:30]=2)O1.N1C=CC=CC=1.O>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:26]3[CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[S:29][CH:30]=3)[N:11]=[C:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:3]=12
Reactant: COc1ncc(Br)c2c(C3CCCC3)n[nH]c12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(Br)cnc(OC)c32)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 44.1 %

Procedure:
A suspension of 4-bromo-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridine (100 mg), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (181 mg), copper(II) acetate (73.6 mg) and pyridine (37.4 mg) in DMF (10 mL) was stirred at room temperature for 4 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (65 mg).
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10](O)[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:19].[OH-].[Na+]>>[Cl:19][C:10]1[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: Oc1cc(C(F)(F)F)nc(C2CCCC2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Temperature: 75 °C
Yield: 88.5 %

Procedure:
2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-ol (2.2 g, 9.47 mmol) was suspended in POCl3 (8.8 ml, 94.7 mmol) and heated to 75° C. for 2 h. After this time, the mixture was added to a chilled sodium hydroxide solution (1 M) and then extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (2.1 g, 90%) as a clear oil. MW=250.65. 1H NMR (CDCl3, 500 MHz) δ 7.46 (s, 1H), 3.42 (quin, J=8.2 Hz, 1H), 2.18-2.07 (m, 2H), 1.99-1.80 (m, 4H), 1.76-1.66 (m, 2H); APCI MS m/z 251 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:56][C:52]1[CH:51]=[C:50]([NH:49][C:22](=[O:23])[CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:26][CH:25]=2)[CH:55]=[CH:54][CH:53]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Reactant: Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4cccc(C)c4)cc3)c2cc1OC
Yield: 55 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. m-Toluidine (0.055 ml) was then added to the solution, and the mixture was heated under reflux for 4 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (102 mg, yield 55%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]=1)=[O:6].[CH2:45]([NH:53][C:54](N1C=CN=C1)=[O:55])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:45]([NH:53][C:54](=[O:55])[NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)=[O:6])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(NCCc1ccccc1)n1ccnc1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)NCCc1ccccc1

Procedure:
The titled compound is prepared from 9-[(1R,2S,3R,4S)-2,3-Dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide using an analogous procedure to Example 42 by replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with imidazole-1-carboxylic acid phenethyl-amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1[CH:5]=[CH:6][S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)(=[O:9])=[O:8].[O-:28][C:29]#[N:30].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1/[CH:5]=[CH:6]/[S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][C:29]([NH2:30])=[O:28])[CH:12]=1)(=[O:9])=[O:8]
Reactant: N#C[O-]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c(N)c2)c(OC)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Nc2ccc(OC)c(NC(N)=O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)-sulfonamide (1 mmol) in glacial acetic acid (10 mL) is added an aqueous solution of potassium cyanate (1 mmol in 2 mL of de-ionized water). The reaction mixture is stirred for 3 h at room temperature. The reaction mixture is then poured into de-ionized water (100 mL) and extracted with ethyl acetate for 3 times. The combined organic layer is then washed with sodium bicarbonate to neutralize acetic acid and then with brine. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed under vacuum to yield the title compound which is purified by column chromatography.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[CH:6]2.CN(C)P(=O)(N(C)C)N(C)C.[O:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[OH:38][C:35]1([C:7]2[N:8]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:14])[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=3)[CH2:36][CH2:37][O:32][CH2:33][CH2:34]1
Reactant: CSc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)cc(C1(O)CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-methylthio-1-benzenesulfonylindole (200 mg) in tetrahydrofuran (5 ml), n-butyl lithium (0.49 ml, 1.61 M) was added at −78° C. under nitrogen atmosphere and the mixture was stirred at −78° C. for 30 minutes, followed by addition of hexamethylphosphoric triamide (0.23 ml), and the mixture was stirred for 15 minutes. Subsequently, tetrahydro-4H-pyran-4-one (0.12 ml) was added thereto and the mixture was stirred at −78° C. for 15 minutes and heated to 15 to 30° C. The reaction solution was then poured into a saturated aqueous ammonium chloride solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) and (methanol:chloroform=1:20) to obtain 39 mg of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]([O:17]COCCOC)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:17])=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)=[O:4]
Reactant: COCCOCOc1c(-c2ccccc2)cc(C(=O)OC)cc1-c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
At ambient temperature, to a stirred solution of 2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.608 g, 4.098 mmol) in CH2Cl2 (16.08 mL) was added portionwise trifluoroacetic acid (16.08 mL). After 1 h, the reaction was diluted with ether (100 mL), washed sequentially with H2O (3×), with sat. aq. NaHCO3 (3×), with brine (3×), dried (MgSO4) and concentrated to give 1.240 g (99%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ3.83 (s, 3H), 7.39-7.50 (m, 6H), 7.55-7.57 (m, 4H), 7.78 (s, 2H), 9.28 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:17][N:18](C)C=O>[C-]#N.[C-]#N.[Zn+2]>[F:16][C:12]1[C:13]([F:15])=[CH:14][C:2]([C:17]#[N:18])=[C:3]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:11]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c(Oc2ccccn2)cc1F
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(F)c(F)cc1Oc1ccccn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of product of Example 136A (0.8 g, 2.76 mmol) in N,N-dimethylformamide (10 ml) were added Zn(CN)2 (0.18 g, 1.52 mmol) and Pd(Ph3)4 (0.32 g, 0.28 mmol) and stirred at 120° C. for overnight. The crude product was purified by flash column chromatography using 0%, 5% and 10% of ethylacetate in hexanes to yield 0.28 g (44%) of product. MS (ESI+) m/z 233 (M+H)+;
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:22][C:23]1[NH:28][C:27](=[S:29])[NH:26][C:25](=[O:30])[CH:24]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+].C(Cl)(Cl)Cl>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:29][C:27]2[NH:26][C:25](=[O:30])[CH:24]=[C:23]([CH3:22])[N:28]=2)[CH:8]=1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: Cc1ccnc(CO)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(CSc2nc(C)cc(=O)[nH]2)c1
Temperature: 0 °C
Yield: 48.1 %

Procedure:
A mixture containing 1.23 g (10 mmol) of 2-hydroxymethyl-4-methylpyridine [Bull. Chem. Soc. Jap. 3, 413 (1955)], 2.1 ml (15 mmol) of triethylamine and 25 ml of chloroform is cooled to 0° C. and 0.85 ml (11.7 mmol) of methanesulfonyl chloride is added under stirring. After stirring for 30 minutes 0.2 g of benzyltriethylammonium chloride and 1.42 g (10 mmol) of 6-methyl-2-thiouracil dissolved in 20 ml of 1N sodium hydroxide solution are added, then the reaction mixture is vigorously stirred at room temperature for 10 hours and worked up in the usual manner. The crude product obtained is crystallized by thoroughly triturating it with diisopropyl ether, m.p.: 157°-158° C. The product obtained is further purified by recrystallization from the mixture of toluene and ethyl acetate to obtain 1.19 g (48%) of the title compound, m.p.: 161°-162° C.
Reaction SMILES: [C:1]([N:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:24][CH3:25])=[C:17]([CH:23]=1)[C:18]([N:20]=[C:21]=[S:22])=[O:19].CO.N1C=CC=CC=1>O1CCCC1>[CH2:8]([C:7]1=[CH:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[S:22]/[C:21]/1=[N:20]\[C:18](=[O:19])[C:17]1[CH:23]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[O:24][CH3:25])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC=NC(C)(C)C
Reactant: COc1ccc(Cl)cc1C(=O)N=C=S
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To the product of Example 1A (1.90 g, 12.2 mmol) in tetrahydrofuran (10 mL) at room temperature under N2 was added the product of Example 1C (2.30 g, 10.1 mmol). After 1 h at room temperature, the reaction was treated with 12 (2.59 g, 10.2 mmol), methanol (30 mL) and pyridine (3 mL) and stirred for 1 hour. The reaction was then partitioned between saturated NaHCO3/diethyl ether with continued stirring overnight. The reaction was diluted further with saturated NaHCO3/diethyl ether, the layers separated and the aqueous phase extracted again with diethyl ether (2×). The organics were combined, dried (MgSO4), filtered and solvent evaporated. Toluene/acetonitrile was added and evaporated 2× to remove excess pyridine and H2O. The crude was flash chromatographed, eluting with diethyl ether:CH2Cl2:hexane (7:3:3) to provide 2.68 g of the desired product with impurities running above and below. This material was dissolved in a minimum of CH2Cl2, hexane added until slightly cloudy and allowed to sit for 4 hours. A white crystalline solid was collected and washed with cold 1:1 CH2Cl2:hexane to provide 962.78 mg of the title compound. The mother liquor was recrystallized from methanol to provide 555 mg additional title compound. The second mother liquor was concentrated to dryness, dissolved in a minimum of CH2Cl2 and flash chromatographed on silica gel, eluting with diethyl ether:CH2Cl2:hexane (7:1:3) to provide an additional 600 mg of the title compound. 1H NMR (300 MHz, CDCl3) δ 0.98 (t, 3H), 1.37-1.49 (m, 2H), 1.65 (s, 9H), 1.67-1.77 (m, 2H), 2.83 (t, 2H), 3.92 (s, 3H), 6.91 (d, 1H), 7.34 (dd, 1H), 7.95 (s, 1H), 8.11 (d, 1H). MS (DCI/NH4+) m/z 381 (M+H)+. Anal. calcd for C19H25ClN2O2S: C, 59.91; H, 6.61; N, 7.35. Found: C, 59.88; H, 6.67; N, 7.42.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]1[O:15][CH2:14][CH2:13][O:5]1
Reactant: OCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(C2OCCO2)c1

Procedure:
2-Chloro-5-nitrobenzaldehyde (18.6 g), ethylene glycol (18.6 ml), p-toluenesulfonic acid (monohydrate), (0.1 g), were refluxed in toluene (150 mL) for 3 hours. Water was removed azeotropically with a Dean-Stark trap. The reaction mixture was then transfered to seperatory funnel, washed with aqueous bicarbonate, water, dried (MgSO4), filtered and evaporated producing 22.2 g of 2-(2- chloro-5-nitrophenyl-1,3-dioxolane as a white solid, m.p. 78-81° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1Cl
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2nccc(C)c2O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1

Procedure:
By following a procedure analogous to Example 27 starting from the 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 24 and 4-methoxyphenylboronic acid, 2-(4-methoxy-phenyl)-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained and is used directly for the deacetylation step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[N+:19]([O-])=O)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:9]=[CH:8][C:7]=1[NH2:19])[CH3:2]
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1N
Reaction time: 4 h

Procedure:
To a solution of [5-(4-Methyl-piperazin-1-yl)-2-nitro-phenyl]-acetic acid ethyl ester (1.10 g, 3.58 mmol) in MeOH (25.0 mL) is added 10% Pd on charcoal (114 mg). The reaction mixture is stirred for 4 h under a hydrogen atmosphere (1 atm.), filtered through a microfilter (0.45 μM), and the filtrate concentrated at reduced pressure to afford the title compound as a red oil. ES+-MS: 278 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[NH:28][CH:27]=[CH:26]2>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:26]2[C:25]3[C:29](=[C:30]([CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=[C:23]([F:22])[CH:24]=3)[NH:28][CH:27]=2)=[C:4]([F:14])[CH:3]=1
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
96 mg (0.44 mmol) of the compound from Example 156A and 0.04 ml (0.53 mmol) of trifluoroacetic acid were added to 100 mg (0.44 mmol) of the compound from Example 87A in 3 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 162 mg (86% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)#[N:2].[H-].[Na+].[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=3)[CH2:32]Cl)=[N:24]2)=[CH:19][CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29](/[CH:28]=[CH:27]/[C:23]3[CH:22]=[CH:21][C:20]4[C:25](=[CH:26][C:17]([Cl:16])=[CH:18][CH:19]=4)[N:24]=3)[CH:30]=1)[CH:11]=[CH:10]2)#[N:2]
Reactant: N#CCCc1cccc2cc[nH]c12
Reactant: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CCCc1cccc2ccn(Cc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)c12
Reaction time: 0.25 h

Procedure:
A solution of 7-(2-cyanoethyl)indole (Example 14a) (4.42 g, 26 mmol) in dimethylformamide (30 ml) was added dropwise to a stirred suspension of sodium hydride (1.3 g, 60% dispersion, 32.5 mmol, washed with hexane under nitrogen) in dimethylformamide (30 ml) at 10°-15° C. The mixture was stirred for 15 minutes at ca 15° C. then a suspension of 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl] benzyl chloride (Example 14b) (10.2 g, 32.5 mmol) in dimethylformamide (60 ml) was added rapidly. The dark mixture was stirred for 5 hours at room temperature, poured onto saturated ammonium chloride solution and extracted with dichloromethane. The extract was dried and evaporated under high vacuum and the residue in dichloromethane (30 ml) was applied to a silica column and eluted with ethyl acetate-hexane (1:2). The product was recrystallised from ethyl acetate-hexane, m.p. 151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.CN(C)CCN(C)C.C([Li])CCC.CN(C)S([Cl:41])(=O)=O>O1CCCC1>[Cl:41][C:11]1[N:12]([CH3:22])[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc(-c2ncn(C)c2-c2ccc(OC)cc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cl)n(C)c2-c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixture of 4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole (10.0 g, 0.034 mol) and N, N, N',N'-tetramethylethylenediamine (three equivalents) in 75 ml of dry tetrahydrofuran was cooled to -78° and treated with n-butyllithium (1.1 equivalents). The mixture was stirred at -78° under nitrogen for one hour and treated with dimethylsulfamoyl chloride (5.5 g, 0.038 mol). The mixture was stirred at -78° for 30 minutes and then overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue triturated with 10% citric acid. The resulting solid was collected by filtration, washed with water, and dried in vacuo to yield 10.3 g (92%) of the title compound, homogenous by tlc (toluene-ethyl acetate, 6:4; Rf=0.56), m.p. 132°-133°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([N:18]=[N+]=[N-])[CH2:15][NH:14]1)=[O:12])[CH3:9].COC([C@@H]1C[C@H](N)CN1[CH2:31][CH:32]1[CH2:37]CCC[CH2:33]1)=O>>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([NH2:18])[CH2:15][N:14]1[CH2:31][CH:32]([CH3:37])[CH3:33])=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1C[C@H](N)CN1CC(C)C

Procedure:
(2S,4S)-4-Amino-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid ethyl ester trifluoroacetate salt in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C11H23N2O2 [(M+H)+] 215, obsd. 215.