Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH3:2].[CH2:15]([O:17][C@H:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[CH:22][CH:21]=1)[CH3:16].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:15]([O:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=2)=[O:28])=[CH:29][CH:30]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:16]
Reactant: CCNCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of N-ethyl-N-[4-(trifluoromethyl)benzyl]amine (0.213 g, 1.05 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g, 1.00 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.337 g, 1.05 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (90 mL) and the organic phase was washed with 5% HCl (2×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.339 g (70%) of a colourless oil.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C([Li])CCC.CCCCCC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.Br[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]([S:27][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:21][CH:20]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: C#C[Si](C)(C)C
Reactant: BrCC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#CC(=Nc1ccc(Cl)cc1)SCC1CCCCC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 11 %

Procedure:
Ethynyl trimethyl silane (0.89 g) was dissolved to dry THF (15 mL), n-butyl lithium/hexane solution (1.6 mol./L; 5 mL) was added thereto at −78° C., and then it was warmed to 0° C. The mixture was cooled to −78° C., THF (4 mL) solution of 4-chlorophenyl isothiocyanate (1.44 g) was added dropwise, and then the mixture was allowed to warm to 0° C. THF (5 mL) solution of bromomethylcyclohexane (1.52 g) was added thereto under ice-cooling, and then the mixture was stirred at 50° C. for 6 hours. The reaction solution was concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain cyclohexylmethyl N-(4-chlorophenyl)-3-(trimethylsilyl)thiopropynimidate (0.34 g).
Reaction SMILES: [N+](C1N=C2N(C=1)CC1(CCN([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)CC1)O2)([O-])=O.FC(F)(F)C(O)=O.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45](C=O)=[CH:44][CH:43]=1.[B-]C#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45]([CH2:22][N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:14]=[O:29])[CH2:21][CH2:20]2)=[CH:44][CH:43]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CCN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 117.8 %

Procedure:
Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidine]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (10 ml) was added followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the solution, methylene chloride (1 ml) and triethylamine (1 ml) were added followed by stirring at room temperature for 5 minutes. The solution was concentrated under reduced pressure and the residue was dissolved in methanol (10 ml). To the solution, 4-trifluoromethylbenzaldehyde (0.23 ml, 1.67 mmol), sodium cyanotrihydroborate (105 mg, 1.67 mmol) and acetic acid (0.1 ml) were added with cooling on ice-bath followed by stirring at room temperature overnight. To the solution, a saturated aqueous sodium hydrogencarbonate solution and methylene chloride were added followed by stirring. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) and crystallized from methylene chloride-diisopropyl ether to afford 1-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin])-1′-yl)-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]ethanone (226 mg, yield 67%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[CH:16]=[CH:15]1)[C:6]([O:8]C)=[O:7].CO.C1COCC1.O.[OH-].[Li+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[CH:16]=[CH:15]1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Cn2ccc3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 72 h
Yield: 91 %

Procedure:
Nitrogen was passed through a solution containing 1.39 g. methyl 3-methoxy-4-(6-nitroindol-1-ylmethyl)benzoate in 1:1 v/v methanol and THF together with 0.86 g. lithium hydroxide monohydrate in 25 ml. water. After 1 minute the reaction mixture was sealed and stirred for 3 days. Solvent was then evaporated. The residue was diluted with water, acidified (1 M hydrochloric acid) and extracted with ethyl acetate. The extracts were washed with water, then with brine and were dried (MgSO4) Evaporation of solvent gave a 3-methoxy-4-[6-nitroindol-1-ylmethyl]benzoic acid in 91% yield as a solid m.p. 243°-245.5° C. which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:44]([CH2:47]C)CC)C.[OH2:49]>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:24][C:47](=[O:49])[NH:44][CH:9]2[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Reactant: CCN(CC)CC
Reactant: O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(Cl)nc2)O1
Yield: 87 %

Procedure:
To a solution of (2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (5.0 g, 13.9 mmol) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (3.3 ml, 15.3 mmol) and triethylamine (2.9 ml, 20.9 mmol), and the mixture was heated under reflux for 1 hr. The reaction solution was allowed to cool and water (200 ml) was added. The mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give (4RS,5SR)-5-(6-chloro-3-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.29 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[NH2:26])=[O:12])=[O:7])=[CH:4][CH:3]=1.[N:29]1([C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[NH:26][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:35])=[CH:43][CH:42]=2)=[O:12])=[O:7])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c(N)c1
Reactant: O=Cc1ccc(C(=O)N2CCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c(NCc2ccc(C(=O)N3CCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
120 mg (0.30 mmol) of methyl 4-[((4-chlorobenzoyl)ethoxycarbonylmethylamino)methyl]-3-aminobenzoate and 66 mg (0.33 mmol) of 4-(1-pyrrolidinecarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.034 ml (0.6 mmol) of acetic acid was added to the solution, and they were stirred at room temperature for 30 minutes. 158 mg (0.75 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)(=O)=O.C(OCC)(=O)C>CN(C=O)C.Cl.O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CCC2CCNCC2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.50 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 24 mg (0.60 mmol) of sodium hydride was added to the obtained solution. After stirring at room temperature for 30 minutes, 184 g (0.60 mmol) of t-butyl 4-(2-((methylsulfonyl)oxy)ethyl)-1-piperidinecarboxylate was added to the obtained mixture, and they were stirred at 70° C. overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 10 ml of 4N solution of hydrogen chloride in dioxane, and the obtained solution was stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the title compound was obtained.
Reaction SMILES: CO[C:3](=[O:40])[C@@H:4]([NH:32][C:33](OC(C)(C)C)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl.Cl.C[O:53][C:54](=[O:72])[C@@H:55]([NH2:71])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][C:64]2[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[CH:65]=2)=[CH:59][CH:58]=1>>[C:41]([N:32]1[C@H:4]([C:3]([NH:71][C@@H:55]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]3[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[CH:65]=3)=[CH:59][CH:58]=2)[C:54]([OH:53])=[O:72])=[O:40])[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:33]1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2)cc1
Agent: Cl
Product: Cc1cc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)ccn1

Procedure:
The title compound (24 mg) was prepared from (S)-2-tert-butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester, which was deprotected according to General Procedure C, subjected to General Procedure V, then acylated with benzoyl chloride according to General Procedure F. Hydrolysis followed General Procedure B and the resulting acid and (S)-2-amino-3-[4-(2-methyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride were reacted according to General Procedures L and B. LCMS (m/z): 845.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1)([O-])=O.[H][H].ONC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1>[Pd]>[NH2:9][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Solvent: COc1ccccc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
300 Parts by weight of anisole are mixed with 27 parts of (97 percent) 1-nitroanthraquinone and 0.2 parts by weight of a palladium/charcoal catalyst (5 percent of Pd on active charcoal) and heated to 130° in an autoclave. At this temperature, hydrogen is blown through until the rate of up-take of the hydrogen has fallen to 10 percent of the original value. At this stage, about 2 percent of overhydrogenated product is present (ascertained by TLC). After interruption of the hydrogen supply, at 130°, 0.4 parts by weight of 1-hydroxylaminoanthraquinone are added and stirring is effected for 30 minutes. The catalyst is separated off at the upper temperature, the filtrate is concentrated and cooled and the 1-aminoanthraquinone is filtered off. No nuclear hydrogenated 1-aminoanthraquinone is present in the mother liquor. 23 Parts of 97 percent pure 1-aminoanthraquinone is obtained.
Reaction SMILES: ClCCN(CC1C=CC=CC=1)CCCl.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][OH:29]>>[OH:23][CH2:24][CH2:25][N:26]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:27][CH2:28][OH:29]
Reactant: OCCNCCO
Reactant: ClCc1ccccc1
Agent: ClCCN(CCCl)Cc1ccccc1
Product: OCCN(CCO)Cc1ccccc1

Procedure:
In one of its aspects, the invention resides in an improved process for preparing N,N-bis(2-chloroethyl)benzylamine by first reacting benzyl chloride with bis(2-hydroxyethyl)amine to produce N,N-bis(2-hydroxyethyl)benzylamine and then reacting N,N-bis(2-hydroxyethyl)benzylamine with thionyl chloride to produce N,N-bis(2-chloroethyl)benzylamine, wherein the improvements comprise adding about one molar equivalent of benzyl chloride to a warmed mixture containing about one molar equivalent of N,N-bis(2-hydroxyethyl)amine and about one molar equivalent of sodium carbonate, the addition rate of benzyl chloride being so as to maintain the exothermic reaction temperature at about 70°-100° C.; maintaining the reaction temperature at about 70° to 100° C. for a short period; adding toluene to the reaction mixture; separating and drying the toluene solution containing N,N-bis(2-hydroxyethyl)benzylamine; adding said dry toluene solution to more than two molar equivalents of thionyl chloride heated to about 65° to 75° C., the rate of addition being so as to maintain the reaction temperature at about 65°-75° C.; treating the reaction mixture with aqueous alkali; and, separating the toluene solution containing a substantially quantitative yield of N,N-bis(2-chloroethyl)benzylamine, which can be used directly in the next step of the synthesis of 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([CH3:33])=[CH:25][CH:26]=2)[N:7]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccc(C)cc2)nc1-c1ccc(C)cc1
Yield: 73.8 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.30 mmol), 4-tolylboronic acid (123 mg; 0.901 mmol) and tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 86 mg (74%) of the title compound. ESI/APCI(+): 389 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1)([O-:35])=[O:34]>ClCCl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])=[CH:40][CH:41]=1)([O-:35])=[O:34]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.2 g, 0.54 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.135 g, 1.34 mmol) (Aldrich), followed by the addition of 1-nitro-4-isocyanato-benzene (0.105 g, 0.64 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with wthyl acetate. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-nitro-phenyl)-amide as a yellow solid (Yield 0.19 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:45])[C:33]=1[O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:5][C:6]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1)(C(OCC=C)=O)[C:7]([O:9]CC=C)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]([CH:6]([CH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:33]([O:34][Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[C:32]([F:45])[CH:31]=1)[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=1)([OH:9])=[O:8]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCC(Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)C(=O)O)cc1
Temperature: 100 °C

Procedure:
9.2 g (14.27 mmol) of diallyl 2-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-2-[2-(4-methoxycarbonylphenyl)ethyl]malonate, 64 mg (0.29 mmol) of palladium(II) acetate and 262 mg (1 mmol) of triphenylphosphine are stirred in 300 ml of dioxane under argon. Then a solution of 4.76 g (47.08 mmol) of triethylamine and 1.64 g (35.67 mmol) of formic acid in 200 ml of dioxane is added dropwise, and the mixture is heated at 100° C. for 2 h. The cooled mixture is concentrated and the crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 3.69 g (49% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Li]C.C([Li])CCC.[CH3:41][S:42]SC>C1COCC1>[CH3:41][S:42][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reactant: CSSC
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cnc2[nH]cc(NC(=O)c3cccnc3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.291 mmol; Example 1A, Step A) was dissolved in THF (20 mL) and cooled to −78° C. MeLi (546 μL, 0.873 mmol) was then added slowly, and the reaction was stirred for 10 minutes. n-Butyl lithium (128 μL, 0.320 mmol) was added next, and the reaction was stirred for an additional 10 minutes, followed by the addition of 1,2-dimethyldisulfane (31.5 mg, 0.335 mmol). The reaction was stirred for 30 minutes and then quenched with water. The reaction was extracted several times with DCM. The organic layer was dried, filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (Biotage Horizon, C-18 25M+, 10-85% CH3CN/water) to provide 50% pure (R)-tert-butyl 1-(5-(methylthio)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate, which was used without further purification.