Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.COCCO>[OH-].[OH-].[Pd+2].CC(O)=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2cnccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCC2CNCCC21
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.55 g) in the mixture solvent of glycol monomethyl ether (40 mL) and AcOH (1 mL) was added a catalytic amount of Pd(OH)2/C. The suspension was heated at 70° C. for 24 h under H2 (2.0 MPa) and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/MeOH) to give the product as viscous liquid (2.64 g, 100.00%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O)[C:3]([O:5][CH3:6])=[O:4].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:19])([CH2:7][O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)COc1ccccc1
Yield: 414 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-(4-toluenesulfonyloxy)propionate (Intermediate A35, 80 g, 0.28 mol), phenol (28 g, 0.029 mol), potassium carbonate (58 g, 0.42 mol), and 250 mL N,N-dimethylacetamide was stirred and heated at reflux for 4 hr. The reaction mixture was cooled, diluted with ethyl acetate, and poured into water. The organic phase was washed with water and concentrated under reduced pressure. The residue was dissolved in hexanes and washed with water, 1 M sodium hydroxide, and a second portion of water. The concentrated solution was distilled at 15 torr (34-37° C.) to yield 25 g (42%) of the methyl 2,2-dimethyl-3-phenoxypropionate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:30](Cl)=[O:31].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([Cl:36])=[C:27]([Cl:26])[CH:28]=1)[CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NC(=O)C(=Cc2c[nH]c3ccc(OCc4ccccc4)cc23)S1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: O=C1NC(=O)C(=Cc2cn(C(=O)c3ccc(Cl)c(Cl)c3)c3ccc(OCc4ccccc4)cc23)S1
Reaction time: 18 h

Procedure:
5-Benzyloxy-3-(2,4-dioxo-thiazolidin-5-ylidene-methyl)-indole (Example 1, Step A; 10 mg) was dissolved in pyridine (1.5 mL) and 3,4-dichlorobenzoyl chloride (35 mg) and a trace of dimethylaminopyridine were added. The mixture was stirred at 50-60° for 18 hrs until the reaction was determined to be complete by TLC. Volatiles were removed under reduced pressure and the residue was washed with water and ether; 10 mg; consistent nmr and ms (m\e 525 (M+1); greater than 95% by HPLC.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:16]=[C:15]([NH:17]C(OC(C)(C)C)=O)[CH:14]=[CH:13][C:12]=1[C:25]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]1)C)=O)(C)(C)C.[ClH:33]>CCOC(C)=O.ClCCl>[ClH:33].[NH2:17][C:15]1[CH:14]=[CH:13][C:12]([C:25]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]2)=[C:11]([CH2:10][NH:8][CH3:6])[CH:16]=1
Reactant: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)cc2CN(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(N)cc2CNC)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 111.9 %

Procedure:
15F (0.173 g, 0.386 mmol) was dissolved in EtOAc (3 mL) and dichloromethane (2 mL), then HCl (4M in dioxane) (2 mL, 8.00 mmol) was added. The reaction mixture was stirred for 6 h at rt. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to give 15G (0.123 g, 99% yield) as an off-white solid. MS (ESI) m/z: 249.1[M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 7.69 (1H, d, J=2.27 Hz), 7.59 (1H, d, J=8.34 Hz), 7.42 (1H, dd, J=8.34, 2.27 Hz), 4.38 (2H, s), 4.14 (2H, q, J=7.07 Hz), 2.84 (3H, s), 1.83 (2H, d, J=3.03 Hz), 1.31-1.39 (2H, m), 1.20 (3H, t, J=7.20 Hz).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([F:20])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:17]=[C:2]([F:1])[C:3]([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=2)=[C:14]([F:20])[CH:15]=1
Reactant: CC(C)(C)CCN
Reactant: NC(=O)c1ccc(Oc2c(F)cc(C=O)cc2F)nc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)CCNCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 80.4 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (278 mg, 1.00 mmol), 3,3-dimethylbutylamine (105 mg, 1.20 mmol), and NaBH4 (57 mg, 1.50 mmol) gave the title compound (292 mg) as a white solid. Mass spectrum (ion spray): m/z=364 (M+1); 1H NMR (DMSO-d6): 8.54 (s, 1H), 8.30 (d, 1H), 8.04 (s, 1H), 7.51 (s, 1H), 7.29 (d, 1H), 7.22 (d, 2H), 3.71 (s, 2H), 2.49 (t, 2H), 1.36 (m, 2H), 0.86 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O>>[CH:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4cc(F)c(F)cc4F)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Nc4cc(F)c(F)cc4F)ncnc32)CC1

Procedure:
4-[4-(2,4,5-Trifluoro-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester was prepared according to General Procedure D by the reaction of 4-[4-(2,4,5-trifluoro-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 4) with trifluoroacetic acid, followed by reaction of the resulting amine with isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.2 Hz), 1.90-1.99 (m, 4H), 3.04-3.15 (m, 3H), 4.08-4.17 (m, 2H), 4.77-4.83 (m, 1H), 4.89-4.94 (m, 1H), 7.69-7.76 (m, 1H), 7.96-7.99 (m, 1H), 8.25 (m, 1H), 8.36 (s, 1H), 10.13 (s, 1H). Mass spectrum MH+=435.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[C:6]1([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)O)[CH3:3].[ClH:26].[OH-].[Na+]>>[ClH:26].[ClH:26].[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)/[CH:17]=[C:6]1/[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[O:9][CH2:10][CH2:11][CH:5]/1[CH2:4][N:2]([CH3:3])[CH3:1]
Reactant: COc1cccc(CC2(O)c3ccccc3OCCC2CN(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(/C=C2/c3ccccc3OCCC2CN(C)C)c1

Procedure:
1.00 g (4RS,5RS)-4-dimethylaminomethyl-5-(3-methoxybenzyl)-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ol (see example 6) and 48 ml 6N hydrocloric acid were stirred at 20° C. for 24 h and at 50° C. for 8 h. The mixture was then rendered alkaline with 6N sodium hydroxide solution and extracted three times with 20 ml ethyl acetate each time. The extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography with ethyl acetate as the eluting agent. After conversion into the hydrochloride with a solution of hydrogen chloride in diethyl ether, 0.72 g (68.6% of th.) of the title compound was obtained.
Reaction SMILES: Cl[C:2]([CH3:9])([CH3:8])[CH:3]([N:6]=[O:7])[CH2:4][CH3:5].Cl.Cl.Cl.[NH2:13][CH2:14][CH:15]([O:25][NH:26][C:27]([CH3:36])([C:29](=[N:34][OH:35])[CH2:30][CH2:31][CH2:32][CH3:33])[CH3:28])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N+:22]([O-:24])=[O:23].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C:2]([CH3:9])([NH:13][CH2:14][CH:15]([CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N+:22]([O-:24])=[O:23])[O:25][NH:26][C:27]([CH3:28])([CH3:36])[C:29](=[N:34][OH:35])[CH2:30][CH2:31][CH2:32][CH3:33])[C:3](=[N:6][OH:7])[CH2:4][CH3:5]
Reactant: CCC(N=O)C(C)(C)Cl
Reactant: CCCCC(=NO)C(C)(C)NOC(CN)Cn1ccnc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCC(=NO)C(C)(C)NOC(CNC(C)(C)C(CC)=NO)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Chloro-4-methyl-3-nitrosopentane (0.52 g, 3.5 mmol, Example 27(A)) was added to a mixture of the hydrochloride title product of step B above (0.62 g, 1.5 mmol) and diisopropylethylamine (0.45 g, 3.5 mmol) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 12 hrs. Acetonitrile was removed on a rotary evaporator and the thick oil obtained was basified with potassium carbonate solution. The light green oil obtained was extracted with ethyl acetate and dried (Na2SO4). Ethyl acetate was removed on a rotary evaporator and the oil obtained was purified by column chromatography (silica gel, ethyl acetate:hexane, 6:4). Fractions containing the product were collected and evaporated to give a colorless oil, which was dried under vacuum to afford a foamy solid. The solid obtained was dissolved in acetonitrile and left at room temperature for 2 hrs. The solid that formed was filtered and recrystallized from acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O>[CH:6](=[N:1][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H](N=Cc1ccccc1)C(O)c1ccccc1

Procedure:
There are prior methods of producing β-phenylalanine derivatives. For example, there is (1) a method which comprises reacting a copper complex of glycine with a benzaldehyde (for example, West German Pat. No. 960,722). The use of the copper salt, however, gives rise to a pollution problem, and the treatment of the waste water becomes troublesome. Moreover, this method generally has the defect of low yields. Another well known method is (2) a method of producing a β-phenylserine which comprises reacting glycine and a benzaldehyde in the presence of an alkali and then treating the product with an acid. For example, according to Kenneth N. F. Shaw and Sidney W. Fox, Journal of American Chemical Society, 75, 3419 (1953), β-phenylserine is obtained in a yield of 70% by reacting glycine and benzaldehyde in the presence of sodium hydroxide in water and treating the product with hydrochloric acid. This method, however, has a serious problem. As stated in the above-cited reference, the sodium salt of N-benzylidene-β-phenylserine, the reaction product of glycine and benzaldehyde, is temporarily precipitated, and the reaction mixture solidifies wholly. As a result, it becomes impossible to stir the reaction mixture mechanically. According to the reaction mechanism as shown in the reaction scheme (1) below, first 1 mole of glycine is condensed with 1 mole of benzaldehyde to form N-benzylidene-β-phenylserine. By treating the N-benzylidene-β-phenylserine with an acid, the desired β-phenylserine is formed. ##STR1##
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1I.[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:17]=1[NH2:18].[I-].C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:18][C:17]1[C:19]([CH3:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=1[Cl:15]
Reactant: Cc1cc(Cl)cc(Cl)c1N
Reactant: Cc1ccc(I)c(CC(=O)N(C)C)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [I-]
Product: Cc1ccc(Nc2c(C)cc(Cl)cc2Cl)c(CC(=O)N(C)C)c1

Procedure:
N,N-Dimethyl-5-methyl-2-iodophenylacetamide (3.5 g, 11.5 mmol) and 2,4-dichloro-6-methylaniline (4.1 g, 23 mmol) are stirred in xylenes (100 ml) with copper powder (0.18 g, 2.9 mmol), copper(l) iodide (0.55 g, 2.9 mmol) and anhydrous potassium carbonate (1.6 g, 11.5 mmol). The reaction is heated to reflux temperature for 48 hours. While still slightly warm (40°) the brown suspension is filtered through a pad of Celite, which in turn is rinsed with toluene (75 ml). The filtrate is evaporated on a rotovap and flash chromatographed on silica gel (Rf 0.30 in 40% EtOAc/hexane) to give N,N-dimethyl-5-methyl-2-(2′,4′-dichloro-6′-methylanilino) phenylacetamide as an off-white crystalline solid, m.p. 119-124°.
Reaction SMILES: CN(C)CC(N1C2C(=CC(OC)=C(NC3N4C(=NC5C(C4=O)=C(F)C=C(F)C=5)C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=3)C=2)CC1)=O.C(N)CC.[CH3:53][N:54]([CH3:104])[CH2:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][C:63]([O:102][CH3:103])=[C:64]([NH:67][C:68]3[N:69]=[C:70]([NH:87][C:88]4[CH:99]=[C:98]([F:100])[CH:97]=[C:96]([F:101])[C:89]=4[C:90]([NH:92][CH2:93][CH2:94][CH3:95])=[O:91])[C:71]4[CH:76]=[CH:75][N:74](S(C5C=CC(C)=CC=5)(=O)=O)[C:72]=4[N:73]=3)[CH:65]=2)[CH2:60][CH2:59]1)=[O:57].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH3:104][N:54]([CH3:53])[CH2:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][C:63]([O:102][CH3:103])=[C:64]([NH:67][C:68]3[NH:73][C:72]4=[N:74][CH:75]=[CH:76][C:71]4=[C:70]([NH:87][C:88]4[CH:99]=[C:98]([F:100])[CH:97]=[C:96]([F:101])[C:89]=4[C:90]([NH:92][CH2:93][CH2:94][CH3:95])=[O:91])[N:69]=3)[CH:65]=2)[CH2:60][CH2:59]1)=[O:57]
Reactant: CCCNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCCN
Product: CCCNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added propylamine (0.183 mL, 2.22 mmol). The resulting mixture was let stir at rt for 5 h at which time it was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid, containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-propylbenzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-propylbenzamide (54 mg, 0.093 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.37 Hz, 3 H) 1.41-1.56 (m, 2 H) 2.19 (s, 6 H) 3.02-3.15 (m, 4 H) 3.19-3.25 (m, 2 H) 3.72 (s, 3H) 4.11 (t, J=8.29 Hz, 2 H) 6.17 (d, J=1.28 Hz, 1 H) 6.76-6.87 (m, 1 H) 6.88-6.97 (m, 2 H) 7.74 (s, 1 H) 8.34-8.43 (m, 1 H) 8.45 (s, 1 H) 8.61 (br. s., 1 H) 10.40 (s, 1 H) 11.28 (br. s., 1 H). (ESIMS (M+H)+=579)
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:14][CH2:15]S(C)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:20].[Na+]>CC(C)=O>[Si:1]([O:8][C@@H:9]([CH2:14][CH2:15][I:20])[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CCI)O[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
To a solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91d, 4.9 g, 15 mmol) in anhydrous acetone was added sodium iodide (11.5 g, 75 mmol). The reaction was heated at reflux for 1.5 h. The reaction was quenched with water and extracted into EtOAc×3. The combined organic phases were washed with brine then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-iodobutanoate (91e, 4.33 g, 12 mmol) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 0.07-0.13 (m, 6H), 0.82-0.99 (m, 9H), 2.09-2.32 (m, 2H), 3.17-3.36 (m, 2H), 3.74 (s, 3H), 4.29 (dd, J=8.08, 4.04 Hz, 1H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:14]1[S:13][C:12]([C:10]2[S:28][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)CCC(=O)c2ccccc2)s1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(-c3ccccc3)s2)s1
Yield: 131.6 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 3.0 grams (0.012 mole) of 1-phenyl-4-(5-methyl-2-thienyl)-1,4-butanedione and 3.0 grams (0.008 mole) of Lawesson's reagent in 100 ml of toluene was heated under reflux for one hour. The reaction mixture was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel using 15% methylene chloride-hexane as eluent. The appropriate fractions were combined and concentrated under reduced pressure to give 2.7 grams of 5'-methyl-5-phenyl[2,2'-bithienyl]; m.p. 102° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:23]([CH2:30][CH3:31])[CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]([CH3:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:20])[NH:13][C:14]([CH3:19])=[CH:15][C:16]=1[CH2:17][OH:18])=[O:8].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:30]([N:23]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:4]1[C:5]([CH3:22])=[C:6]([C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:20])[NH:13][C:14]([CH3:19])=[CH:15][C:16]=2[CH2:17][OH:18])=[O:8])[CH:21]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:3]=1)[CH3:31]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(CO)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(CO)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 20.4 %

Procedure:
To a stirred solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (250 mg, 0.5 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (230 mg, 7.6 mmol) in dioxane (5 mL), aqueous 2M Na2CO3 solution (0.9 mL, 1.8 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (57 mg, 0.05 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (60 mg, 25%). LCMS: 589.35 (M+1)+; HPLC: 95.58% (@ 254 nm) (Rt; 3.524; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.22 (t, 1H), 7.57 (d, 2H, J=7.6 Hz), 7.38 (d, 2H, J=5.6 Hz), 7.36 (s, 1H), 7.21 (s, 1H), 6.16 (s, 1H), 5.28 (m, 1H), 4.52 (d, 2H, J=4.8 Hz), 4.25 (d, 2H, J=3.6 Hz), 3.81-3.83 (m, 2H), 3.57 (m, 4H), 3.48 (s, 2H), 3.01-3.09 (m, 3H), 2.36 (m, 4H), 2.23 (s, 3H), 2.15 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 1.23 (m, 2H), 0.82 (t, 3H, J=6.4 Hz).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=N[C:7]=2[CH:6]=1)[NH2:4].[C:14](C1C=C2C(=CC=1)NC=C2)#N>>[OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[NH:9][CH:10]=[CH:14]2)[NH2:4]
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: NC(=NO)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from 5-cyanoindole (2 g; 14.07 mmol) as a brown solid (2.4 g, 97%). HPLC (Method A), Rt 0.95 min (Purity: 88.8%). LC/MS (Method B): 176.1 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>CN(C)C=O>[CH:33]1([CH2:36][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])[CH2:35][CH2:34]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC2CC2)CC1
Yield: 27 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (27%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 493.2 (M+H)+.