Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2.67 g (8.3 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid and 1.73 ml (12.5 mmol) of triethylamine were dissolved in 50 ml of THF. 0.95 ml (9.9 mmol) of ethyl chloroformate was added to the obtained solution, and they were stirred for 15 minutes. The obtained precipitate was removed by the suction filtration. 1 g of ice and 0.47 g (12.5 mmol) of sodium borohydride were added to the filtrate under cooling with ice, and they were stirred overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])=[C:28]([C:41](=[O:45])[CH:42]=[N+]=[N-])[N:27]=[CH:26]2)[C@H:11]1[F:46])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:47].C(OCC)C>ClCCl>[C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])=[C:28]([C:41](=[O:45])[CH2:42][Cl:47])[N:27]=[CH:26]2)[C@H:11]1[F:46])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: [N-]=[N+]=CC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N2C(=O)c3ccccc3C2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
The solid containing compound (14) obtained in step (5) above was dissolved in dichloromethane (5 ml), to which was then added a 1M hydrogen chloride-diethyl ether solution (0.5 ml), and the resultant mixture was allowed to react for 0.5 hours to produce the titled compound (15). The reaction solution so obtained was diluted with dichloromethane and washed with water, and the organic layer obtained was dried over anhydrous sodium sulfate and then concentrated to yield the titled compound (15) as a solid (190 mg). Yield from compound (12): 90%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH:52]1[CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH:52]1[NH:51][C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)=[O:20]
Reactant: NC1Cc2ccccc2C1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4Cc5ccccc5C4)cc3)c(C#N)cc21
Reaction time: 3 h
Yield: 75.3 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (from Example 7, Step B) (12 mg, 0.034 mmol), HBTU (15 mg, 0.041 mmol) were diluted with N-methylpyrrolidone (1 mL) followed by the addition of 2-aminoindan (4.5 mg, 0.034 mmol), N,N-diisopropylethylamine (0.015 mL, 0.085 mmol) and DMAP (1.2 mg, 0.010 mmol). After stirring for 3 hours, the reaction was loaded directly onto a Biotage 12i cartridge eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (12 mg, 75% yield).
Reaction SMILES: C([C@@H:8]1[CH2:12]OC(=O)[N:9]1[C:14](=[O:35])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][C:21]=1[Cl:34])CC=O)C1C=CC=CC=1.[NH:36]1[C:44]2[CH2:43][CH2:42][C@H:41](N)[CH2:40][C:39]=2[CH:38]=[N:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:34][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][C@@H:15]1[CH2:12][CH2:8][N:9]([C@H:41]2[CH2:42][CH2:43][C:44]3[C:39](=[CH:38][NH:37][N:36]=3)[CH2:40]2)[C:14]1=[O:35]
Reactant: O=CC[C@@H](Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: N[C@H]1CCc2[nH]ncc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
Add (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-4-oxo-butyraldehyde (Preparation 94) (1.13 mmoles; 580.00 mg) (dissolved in 5 ml dichloromethane) to (S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amine 1.13 mmoles; 154.69 mg) dissolved in 5 ml Acetonitrile (5 mL). Cool the mixture in an ice water bath and add sodium triacetoxyborohydride (3.38 mmoles; 716.94 mg) portion wise. Remove the cooling bath and warm the mixture to ambient. Cool the mixture in an ice water bath and quench with 10 ml saturated sodium bicarbonate. Add 15 ml of ethyl acetate followed by 10 ml of brine. Charge the solution to a separatory funnel and separate the organic layer, dry over magnesium sulfate, filter, and concentrate to ⅓ volume. Add a seed crystal of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-(S)-4,5,6,7-tetrahydro-2H-indazol-5-yl-pyrrolidin-2-one. Stir the solution at ambient temperature for 16 hours. Crystallization occurs and cool the mixture in an ice-water bath. Filter the cold mixture, collect the solid, and dry to give 284 mg of a white solid-crop A. LCMS=100% (M+1) at 458 amu. To the filtrate (now dry after evaporation), add 10 ml of MTBE to crystallize the rest of the product to obtain 89 mg white solid-crop B. LCMS=100% (M+1) at 458 amu 0.373/0.52=71.7%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[S:28][C:27]=1CO>C(Cl)Cl>[Br:24][CH2:20][C:27]1[S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]=1[Cl:25]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1sc2ccccc2c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1c(CBr)sc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of triphenylphosphine (1.74 g, 6.62 mmol) in dry CH2Cl2 (6 mL) was added dropwise to a stirred solution of carbon tetrabromide (2.20 g, 6.62 mmol) and (3-chloro-1-benzothien-2-yl)methanol (0.94 g, 4.73 mmol) in dry CH2Cl2 (35 mL) at 0° C. under N2. The reaction was allowed to warm to room temperature and was stirred for 4 h then concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 nm, 0-25% EtOAc in hexanes gradient) to afford 2-(bromomethyl)-3-chloro-1-benzothiophene. Rf=0.93 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 7.81 (dd, J=1.3, 7-1 Hz, 1H); 7.78 (dd, J=1.2, 7.2 Hz, 1H); 7.47-7.41 (m, 2H); 4.81 (s, 2H).
Reaction SMILES: NN.[C:3]([O:7][C:8](=[O:37])[NH:9][C@H:10]([CH2:25][N:26]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:11][C:12]([CH3:24])([CH3:23])[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:6])([CH3:5])[CH3:4].C(OCC)C>C1COCC1.C(O)C>[C:3]([O:7][C:8](=[O:37])[NH:9][C@H:10]([CH2:25][NH2:26])[CH2:11][C:12]([CH3:24])([CH3:23])[CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(CCOCc1ccccc1)C[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Hydrazine (66.6 ml of a 1M solution in THF, 66.6 mmol) is added to a suspension of [(S)-5-benzyloxy-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pentyl]-carbamic acid tert-butyl ester (4 g, 8.32 mmol) in ethanol (100 ml), and the resulting solution is heated at 40° C. overnight. A fluffy white precipitate forms. The reaction is allowed to cool to room temperature and diethyl ether (100 ml) is added and the resulting white suspension cooled at 0° C. for 30 minutes. The white precipitate is removed by filtration and the solvent removed in vacuo. The residue is then stirred with diethyl ether (100 ml) for 1 hour, filtered and the solvent is removed in vacuo to afford ((S)-1-Aminomethyl-5-benzyloxy-3,3-dimethyl-pentyl)-carbamic acid tert-butyl ester as a pale yellow oil; [M+H]+ 351.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.[CH2:31]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:39]3[CH2:38][CH2:37][N:36]([S:33]([CH2:31][CH3:32])(=[O:34])=[O:35])[CH2:41][CH2:40]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with 1-ethanesulfonyl-piperazine to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone in an analogous manner as described in example 1. LR-MS: 621.2 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([N:22]([CH3:31])[CH3:21])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)c1cccc(CN)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)c1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-dimethylamino-benzylamine (58.3 mg, 0.39 mmol). The title compound was obtained as a solid (98.2 mg, 51% yield). 1H NMR (400 MHz; d6-DMSO) δ: 9.31 (1H, m), 8.98 (2H, s), 8.49 (1H, s), 7.11 (1H, m), 6.63 (2H, m), 6.55 (1H, m), 4.33 (2H, m), 2.86 (6H, s). MS m/z: 483.10, 485.11 [M+H]+.
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>O.C1(C)C=CC=CC=1>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH:9]2[CH2:10][CH2:11][N:6]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=3)[CH2:7][CH2:8]2)=[CH:23][CH:22]=1)#[N:21]
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1
Reactant: N#Cc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)cc3)CC2)cc1
Reaction time: 18 h
Yield: 83.9 %

Procedure:
To an N,N-dimethylformamide (150 mL) solution of 10.2 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile were sequentially added 11.2 g of potassium carbonate and 9.72 g of 4-(3-bromopropoxy)benzonitrile at room temperature, which was then stirred at the same temperature for 18 hours. Toluene and water were added to the reaction mixture. The precipitate was collected by filtration to provide 13.7 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)benzonitrile as white solid form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[NH:9][CH:8]=[C:7]([C:20]#[N:21])[C:6]2=O.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:6]1[C:5]2[C:10](=[CH:11][C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)c(C#N)c[nH]c2cc1N1CCN(C)CC1
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)c(C#N)cnc2cc1N1CCN(C)CC1
Temperature: 105 °C

Procedure:
A reaction mixture of 0.3 g (1.01 mmol) of 6-methoxy-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbonitrile in 5 mL of phosphorus oxychloride is heated at 105° C. for 45 minutes. After cooling, the mixture is concentrated to dryness in vacuo to give a brown solid. To this is added 5 mL toluene, and the solution is concentrated to dryness again. Dropwise, an ice-cooled saturated aqueous sodium carbonate solution is added to the residue. This mixture is extracted with 5×25 mL of a 95:5 mixture of methylene chloride/methanol. The organic layer is dried over magnesium sulfate. The magnesium sulfate is removed by filtration, and solvent is removed in vacuo to provide 0.255 g of 4-chloro-6-methoxy-7-(4-methylpiperazin-1-yl)-quinoline-3-carbonitrile as a yellow solid, mp 177-179° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[CH2:13](O)[CH2:14][CH2:15][OH:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:16][CH2:15][CH2:14][CH2:13][O:6]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: OCCCO
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Product: O=[N+]([O-])c1ccc(C2OCCCO2)cc1O
Yield: 94.9 %

Procedure:
3-Hydroxy-4-nitro-benzaldehyde (7.5 g, 44.9 mmol) is treated with 1,3-propanediol (5.1 g, 67.3 mmol) according to the procedure of Example 1 to give 2-(3-hydroxy-4-nitro-phenyl)-1,3-dioxane (9.6 g, 95% yield) oil.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[NH2:3][C:4]1[C:13]([I:1])=[CH:12][C:11]([F:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(F)cc(I)c1N
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Iodine (3.6 g, 14.2 mmol) was added to a mixture of methyl 2-amino-5-fluorobenzoate (2.4 g, 14.2 mmol), silver sulfate (4.42 g, 14.2 mmol) and ethanol (30 mL) at room temperature. The mixture was stirred under nitrogen for 1 h, and then quenched with a saturated solution of sodium bicarbonate, extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10 hexanes/ethyl acetate) to afford methyl 2-amino-5-fluoro-3-iodobenzoate (3.9 g, 93%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.66-7.58 (m, 2H), 6.21 (br s, 2H), 3.89 (s, 3H); 19F NMR (282 MHz, CDCl3) δ 127.87; MS (ESI+) m/z 296 (M+H).
Reaction SMILES: CC(CC(C)C)=O.[C:8]1([C:14]2([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>O>[C:8]1([C:14]2([NH:19][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC1(c2ccccc2)CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)C(=O)NC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Into a 500 ml four-necked flask, there were charged methylisobutylketone (150 ml), 1-phenylcyclopentylamine (24.3 g) and triethylamine (16.0 g), and trimethylacetyl chloride (18.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, water (200 ml) was added thereto and the reaction mixture was gradually heated to remove methylisobutylketone, followed by cooling at room temperature. The precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to give N-(1-phenylcyclopentyl)trimethylacetamide (33.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=O)[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[NH:12][C:11]2=[O:17])[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]
Reactant: Nc1ccc(-c2cccc3c2CC(=O)N3)cn1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(N)nc4)c32)c1CCCN1CCN(C)CC1

Procedure:
4-(6-Aminopyridin-3-yl)-1,3-dihydroindol-2-one (56 mg, 0.25 mmol) was condensed with 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (88 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]=[C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The resultant 4-benzyloxycarbonyl-1-{[1-(tert-butoxycarbonyl)-4-piperidinylidene]amino}-2-piperazinone was dissolved in methanol (40 ml), combined with acetic acid (1.2 g) with cooling on ice, followed by sodium cyanoborohydride (943 mg), and then stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried, concentrated and purified by a column chromatography (ethyl acetate) to obtain 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone (3.7 g) as a colorless amorphous material.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[O:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)[CH:33]([CH3:35])[CH3:34]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:32][CH:33]([CH3:35])[CH3:34])[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: CC(C)Oc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Oc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 38.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-isopropoxylphenylboronic acid (32 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with 30% ethyl acetate/hexanes then by RP HPLC to afford the product as a white solid (22 mg, 38%). MS m/e 465.27 (M+H+)
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][NH:13]2)=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:8]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:8]=1
Reactant: CC(C)CI
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
An N,N-dimethylformamide (5 ml) suspension of 2-chloro-6-((S)-3-methylmorpholin-4-yl)-9H-purine (839 mg, 3.31 mmol), 1-iodo-2-methylpropane (730 mg, 3.97 mmol), and potassium carbonate (594 mg, 4.30 mmol) was stirred at 50° C. for 4 hours. The reaction mixture was returned to room temperature. Ethyl acetate was added to the reaction mixture and the resulting mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=7:3) to give the title compound (868 mg, 85%) as an amorphous substance.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:10]([OH:18])([CH2:15][CH:16]=[CH2:17])[C:11]([CH3:14])(C)C)([CH3:9])(C)C.C1(=O)CCCCC1.C(OCC)C>CCCCC.C1COCC1.[Zn+2].[Br-].[Br-]>[CH2:15]([C:10]1([OH:18])[CH2:6][CH2:9][CH2:1][CH2:14][CH2:11]1)[CH:16]=[CH2:17]
Reactant: C=CCC(O)(C(C)(C)C)C(C)(C)C
Reactant: [Li]CCCC
Agent: [Br-]
Agent: [Zn+2]
Solvent: O=C1CCCCC1
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=CCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.94 ml of a 1.4-molar solution of n-butyllithium (2.71 mmol) in pentane were added dropwise at 0° C. under argon for 2 minutes to a stirred solution of 500 mg (2.71 mmol) 3-tert-butyl-2,2-dimethylhex-5-en-3-ol in 4 ml THF. The solution obtained was stirred for 15 minutes, and then a solution of 610 mg (2.71 mmol) ZnBr2 in 2 ml THF and 280 μl (2.71 mmol) cyclohexanone were added. The reaction mixture was stirred for 4 hours and heated to room temperature. Subsequently, it was processed analogous to Example 1. The raw product obtained was cleaned by means of a silica column with 20% diethyl ether/light gasoline. There was obtained the alcohol as a colorless oil.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:3]2[CH:2]=[C:1]([CH3:12])[CH:6]=[CH:5][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1cccc(C2CCCN2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccc(C)c2)cc1

Procedure:
The title compound, off-white solid, m.p. 79° C. and MS: m/e=315 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-m-tolyl-pyrrolidine and toluene-4-sulfonyl chloride.