Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=3[N:9]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:8]2=[NH:28])=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:77][C:78]1[CH:83]=[CH:82][C:81]([C:84]2[CH2:89][CH2:88][C:87]([CH3:91])([CH3:90])[CH2:86][C:85]=2[CH2:92][N:93]2[CH2:98][CH2:97][NH:96][CH2:95][CH2:94]2)=[CH:80][CH:79]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:77][C:78]1[CH:83]=[CH:82][C:81]([C:84]2[CH2:89][CH2:88][C:87]([CH3:90])([CH3:91])[CH2:86][C:85]=2[CH2:92][N:93]2[CH2:94][CH2:95][N:96]([C:2]3[CH:30]=[CH:29][C:5]([CH2:6][N:7]4[C:11]5[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=5[N:9]([CH2:17][CH2:18][CH2:19][O:20][C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)[C:8]4=[NH:28])=[CH:4][CH:3]=3)[CH2:97][CH2:98]2)=[CH:80][CH:79]=1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccc(F)cc2n1Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(Cn4c(=N)n(CCCOc5ccc(F)cc5)c5ccc(F)cc54)cc3)CC2)C1
Temperature: 95 °C
Yield: 43.5 %

Procedure:
To a degassed solution of 3-(4-bromo-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (0.060 g, 0.11 mmol) in toluene (2 ml) at rt under nitrogen was added Pd(OAc)2 (0.9 mg, 4.0 μmol) and BINAP (4.7 mg, 7.6 μmol). Nitrogen was bubbled through the mixture for 10 min before a degassed solution of 1-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine (49 mg, 0.15 mmol) in toluene (1 ml) was introduced. After 5 min Cs2CO3 (0.41 g, 1.27 mmol) was added. During all additions nitrogen was continuously bubbled through the reaction. Once the additions were completed the reaction vessel was sealed and then heated to 95° C. where it was maintained for 18 h. After this time, the reaction was cooled to rt and filtered through Celite® and the collected solids were washed with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure and the crude product was purified by preparative HPLC. The purified product was partitioned between a saturated solution of NaHCO3 and dichloromethane and the organic phase was separated. The aqueous layer was extracted with additional dichloromethane and then the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 3-(4-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (34 mg, 45%). HPLC-MS 710 [M+1]+, 348.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1)#[N:2].[H-].[Na+].[Na].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[O:26][CH3:25])[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]2=1)#[N:2]
Reactant: COc1ccccc1CCl
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1Cn1c2c(c3cc(C#N)ccc31)CC(NC(=O)C(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Follow the procedures essentially as described in Example 104, above, using N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (3.38 g, 12 mmol) and treating with sodium hydride (580 mg, 14A mmol). Cool the formed sodium salt in a dry ice/acetonitrile bath and add 2-methoxybenzylchloride (1.84 mL, 13.2 mmol) in DMF (2 mL) at −35 to −30° C. Remove the bath and allow the reaction to warm to ambient temperature over 3 h with stifling. Add water (250 mL) dropwise, cooling in an ice bath while stirring for 30 min. Filter the resulting precipitate and dry under house vacuum at 45° C. for 18 h. Triturate and sonicate the material in diethyl ether for 1.5 h, filter and dry to provide 3.98 g (83%) of an off-white solid.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:42])[C@H:13]([CH3:41])[NH:14][CH:15](C(OCC)=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2C=CC=CC=2)=[O:27])[CH2:22][CH2:21]1)(C)(C)C.[BrH:44].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:44].[BrH:44].[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C@H:13]([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([OH:43])=[O:5])=[O:42])[CH3:41])[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(CCCCCN[C@@H](C)C(=O)N2CCC[C@H]2C(=O)O)CC1
Reaction time: 1 h

Procedure:
In 1.5 ml of acetic acid is dissolved 0.66 g of N-[N-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-L-proline tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction solution, followed by shaking, and the precipitate is rinsed twice with 50 ml of ethyl ether. The resulting yellow, viscous material is dissolved in 5 ml of water, and the solution is extracted with 10 ml of ethyl acetate. The aqueous layer is lyophilized to give 0.4 g of N-[N-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl-L-proline.dihydrobromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:21])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-propyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.27) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 469.5 [(M+H)+]; mp 214-217° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[C:17]([C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>S(=O)(=O)(O)O>[NH:20]1[C:19]([C:17]2[CH:16]=[CH:15][C:11]3[C:12](=[O:13])[C:6]4[C:1]([S:7](=[O:9])(=[O:8])[C:10]=3[CH:18]=2)=[CH:2][CH:3]=[CH:4][CH:5]=4)=[N:23][N:22]=[N:21]1
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)cc1S(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21

Procedure:
2-Phenylsulphonyl-4-(5-tetrazolyl)benzoic acid (200 mg) was heated with concentrated sulphuric acid (10 ml) for 5 hr. at 120° C. After cooling and dilution with water, a solid product seperated and was filtered off, washed with water, and recrystallised from acetic acid to give 3-(5-tetrazolyl)thioxanthone-10,10-dioxide, identified by its infrared spectrum.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:8][C@H:7]1[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCOCC1
Reaction time: 1 h

Procedure:
To a solution of (1R,2R,4R)-4-hydroxy-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester (1.0 mmol) in dichloromethane (5 ml) was added at 5° C. triethylamine (2.2 mmol) and methanesulfonyl chloride (2.2 mmol) and stirring was continued for 1 h. The mixture was partitioned between 1 N aqueous HCl and ethyl acetate, the organic layer was dried, evaporated and chromatographed on silica using ethyl acetate to give (1R,2R,4R)-4-methanesulfonyloxy-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester as a colorless oil. MS: 350.4 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1.O>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:1]([C:13]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:5])[C:15]=2[CH:14]=1)([O-:4])=[O:2]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46°-50° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][CH2:28][CH2:29][OH:30])[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:45]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][CH2:28][C:29]([OH:45])=[O:30])[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:34]=[C:35]([CH3:40])[CH:36]=[C:37]([CH3:39])[CH:38]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCCO)c(Cl)cc3[nH]c2=O)c1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-hydroxy-propyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (176 mg in 3.0 mL methylene chloride) was added 20 mg powdered 4Å sieves, 73 mg of 4-methylmorpholine-N-oxide, followed by 11 mg tetrapropylammonium perruthenate(VII) and the mixture stirred at room temperature. After 3 hours, the solvent was removed in vacuo and the crude aldehyde product resolvated in a mixture of tert-butanol (2 mL) and sodium phosphate (1 mL of a 1.25M solution). To this was added 1.86 mL of a 1M aqueous solution of potassium permanganate. After 30 minutes, the mixture was extracted with ethyl acetate, dried over sodium sulfate and purified by flash chromatography on silica gel (hexane:ethyl acetate, 1:1; then methylene chloride:methanol, 90:10) to give the title compound (107 mg).
Reaction SMILES: CN1C=CC=N1.C([Li])CCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2(C#N)[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.ClC1C=CC(C2([C:36]([C:38]3[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=3)=[NH:37])CCC2)=CC=1.[BH4-].[Na+].Cl>CCCCCC.CCOCC.O>[ClH:12].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([NH:37][CH2:36][C:38]3[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=3)[CH2:20][CH2:21][CH2:22]2)=[CH:17][CH:18]=1
Reactant: Cn1nccc1C(=N)C1(c2ccc(Cl)cc2)CCC1
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Agent: Cn1cccn1
Agent: [BH4-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: Cn1nccc1CNC1(c2ccc(Cl)cc2)CCC1

Procedure:
1-Methylpyrazole (4.8 g) was added to a mixture of dry ether (60 ml) and a 1.7M solution of butyllithium in hexane (30 ml) under nitrogen at a temperature of less than 5° C. N,N,N'N'-Tetramethylethylenediamine (TMEDA) (8.3 g) was added and the mixture stirred at 0°-5° C. for one and three quarter hours and then 1-(4-chlorophenyl)cyclobutanecarbonitrile (6.0 g) was added and the mixture stirred for 90 minutes at a temperature in the range 0 to 5° C. Water was added and the reaction mixture extracted with ether. The extract was washed, dried and evaporated to give an oil which is [1-(4-chlorophenyl)cyclobutyl](1-methylpyrazol-5yl)methanimine. The imine was stirred with a mixture of sodium borohydride (2 g) in diethyleneglycoldimethyl ether (100 ml) under nitrogen at 95° C. for two hours. The mixture was poured into water and extracted with ether. The extract was washed, dried and evaporated to give a residue which was dissolved in dry ether. Hydrogen chloride gas was passed through the ethereal solution to give a hydrochloride salt of [1-(4-chlorophenyl)cyclobutyl](1-methylpyrazol-5-yl)methylamine hydrochloride (m.p. 316°-318° C.) containing 1.25 moles of hydrochloride and 0.25 moles of water.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:34]5[C:29]([O:28][CH3:27])=[N:30][CH:31]=[CH:32][CH:33]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc(C)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
A solution of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing 2-methoxypyridin-3-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol). Saturated Na2CO3 solution was added (100 μL) and the reaction was stirred at 80° C. overnight. The reaction was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate in hexanes) to obtain 50 mg (55%) of a clear oil. ESI-MS m/z calc. 453.4. found 454.5 (M+1)+. Retention times: 1.9 minutes. H NMR (400 MHz, DMSO) 8.81 (s, 1H), 8.22 (dd, J=1.9, 5.0 Hz, 1H), 7.84 (s, 1H), 7.57-7.53 (m, 2H), 7.38-7.31 (m, 2H), 7.05 (dd, J=5.0, 7.2 Hz, 1H), 3.78 (s, 3H), 2.29 (s, 3H), 1.89 (s, 3H), 1.50-1.47 (m, 2H), 1.16-1.13 (m, 2H)
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](Cl)=[O:51])=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:50]([C:49]1[CH:53]=[CH:54][C:46]([F:45])=[CH:47][CH:48]=1)=[O:51]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH3:12].[BH4-].[Na+].[OH-].[Na+]>>[CH2:11]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:10][C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1ccc(C=O)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(CNc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-ethylbenzaldehyde (2.95 g; 3.02 ml; 22 mmol; 1.1 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 3.31 g (65.9%); MS m/z: 252.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.56 (q, 2H, 3J=7.6 Hz); 4.22 (s, 2H); 5.98 (br s, 1H); 6.51 (br s); 6.61 (dd, 1H, 4J=2.2 Hz, 3J=8.6 Hz); 7.13-7.14 (m, 2H); 7.26-7.29 (m, 3H); 7.83 (s, 1H); 11.84 (br s, 1H)
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=1[CH2:36][CH2:37][O:38][C:39](Cl)=[O:40])([O-:26])=[O:25].CC(O)C.N#N>C(Cl)Cl>[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:28]=1[CH2:36][CH2:37][O:38][C:39]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])=[O:40])([O-:26])=[O:25]
Reactant: O=C(Cl)OCCc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: N#N
Solvent: CC(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)OCCc3c([N+](=O)[O-])cccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: -50 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
Thymidine (1 g, 4.13 mmol) was co-evaporated with pyridine (3×10 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine (15 ml, see above) and cooled down to -50° C. A solution of 2-(2,6-dinitrophenyl)ethoxycarbonyl chloride (1.7 g, 6.19 mmol) in CH2Cl2 (15 ml, dist. over CaH2) was added dropwise thereto for 1 h. After a further 3.5 h stirring in conditions of i-PrOH/N2 cooling (-50° to -20° C.), the mixture was diluted with CH2Cl2 (50 ml) and washed with H2O (50 ml). The aqueous phases were post-extracted with CH2Cl2 (2×50 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure and co-evaporated using toluene (3×50 ml). The crude product (2.66 g) was treated with CH2Cl2 /MeOH 2:1 (60 ml) at boiling temperature. The white precipitate obtained was filtered by suction and recrystallized from MeOH (25 ml). 5'-O-(2-(2,6-dinitrophenyl)ethoxycarbonyl)thymidine (855 mg, 43%) was obtained as a colorless solid. The combined filtrates were concentrated under reduced pressure to a dry state and purified by column chromatography (1.4 g crude product, 56 g SiO2 17×3 cm, CH2Cl2 /MeOH 100:5 1240 ml, 100:7 105 ml, 100:10 330 ml). 5'-O-(2-(2,6-dinitrophenyl)ethoxcarbonyl)thymidine (691 mg, 34.8%) was obtained as a colorless solid. The yield of 5'-O-(2-(2,6-dinitrophenyl)ethoxycarbonyl)thymidine totalled 1.55 g (78%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:5][CH:4]=1.[CH:27]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:13]2[CH2:14][CH2:15][N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:17][CH2:18]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCNCC2)cc1
Reactant: BrC1CCCC1
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C3CCCC3)CC2)cc1

Procedure:
Starting materials: 50ELH87 (0.25 g, 0.71 mmol, 1.0 eq.), Cyclopentylbromide (0.288 g, 3.0 eq.).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[B]1OC2C(=CC=CC=2)O1.[NH2:30][C:31]1[C:36](I)=[C:35]([NH2:38])[N:34]=[CH:33][N:32]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:31]1[C:36]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)=[C:35]([NH2:38])[N:34]=[CH:33][N:32]=1
Reactant: Nc1ncnc(N)c1I
Reactant: CC(C)c1ccc(C#Cc2ccc(C(C)C)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [B]1Oc2ccccc2O1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C=C(c2ccc(C(C)C)cc2)c2c(N)ncnc2N)cc1
Yield: 28 %

Procedure:
1,2-Bis(4-(2-propyl)phenyl)acetylene (11.40 g, 43 mmol) was dissolved in 50 mL THF, catecholborane (1 M, 50 mL) in THF was added, and the mixture was heated at reflux for 30 hours. The mixture was cooled, then 4,6-diamino-5-iodo-pyrimidine, 30 mL saturated aqueous sodium bicarbonate, 20 mL 3N aqueous sodium hydroxide, and 1.00 g (0.87 mmol) tetrakis(triphenylphosphine)palladium(0) were added. The mixture was heated to reflux for 18 hours, cooled, diluted with water, then extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, and the solvent evaporated. The residue was chromatographed on silica gel with 2.5% to 5% (19:1 ethanol:ammonium hydroxide) in ethyl acetate to give the desired product (4.53 g, 28% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][N:44]([CH2:56][CH2:57][OH:58])[N:43]=2)=[CH:38][CH:37]=1)([O-:35])=[O:34]>>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:46]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)(=[O:26])=[O:25])[C:9]([C:11]5[CH:12]=[CH:13][C:14]([CH2:17][N:18]6[CH2:19][CH2:20][O:21][CH2:22][CH2:23]6)=[CH:15][CH:16]=5)=[CH:10][C:3]=34)=[CH:45][N:44]([CH2:56][CH2:57][OH:58])[N:43]=2)=[CH:40][CH:41]=1)([O-:35])=[O:34]
Reactant: CC1(C)OB(c2cn(CCO)nc2-c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccc(CN3CCOCC3)cc2)cc2c(Br)ccnc21
Product: O=[N+]([O-])c1ccc(-c2nn(CCO)cc2-c2ccnc3c2cc(-c2ccc(CN4CCOCC4)cc2)n3S(=O)(=O)c2ccccc2)cc1

Procedure:
Following the procedure for Intermediate 100 using 4-bromo-2-[4-(N-morpholinylmethyl)phenyl]-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine and 3-(4-nitrophenyl)-1-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 665.2