Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.O.[C:34](O)(=O)[CH:35]=[O:36].ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O.C(N(CC)CC)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH2:34][CH2:35][OH:36])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=CC(=O)O
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1nc2c(s1)CNC(CCO)C2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
In a similar manner to Example 91 except for the use of 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (132 mg) and glyoxylic acid hydrate (82 mg) as the raw materials, the reaction was conducted, whereby a crude product was obtained. The product was suspended in tetrahydrofuran (50 ml), followed by the addition of triethylamine (0.22 ml) and ethyl chloroformate (0.03 ml) under ice cooling. After stirring at room temperature for 15 minutes, sodium borohydride (50 mg) and water (10 ml) were added and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, washed with saturated saline and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=100:3). The purified product was dissolved in saturated ethanol hydrochloride (1 ml), followed by concentration under reduced pressure. The concentrate was pulverized and washed in ethyl acetate, whereby the title compound (52 mg, 33%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[S:48])[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)ncc1[N+](=O)[O-]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1cc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)ncc1[N+](=O)[O-]

Procedure:
1-[4-(4-Methyl-5-nitro-pyridin-2-ylamino)-piperidin-1-yl]-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butan-1-one (23 mg; 0.043 mmol, prepared in accordance with Example 71) is reacted with Lawesson's reagent (9 mg; 0.043 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (9 mg; 0.016 mmol). The structure was confirmed using Protocol 1-B. Calculated mass=551; observed mass=551; HPLC retention time=4.45 min.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]=1I.CC1CCCO1.C([Mg]Cl)(C)C.O1CCCC1.[Cl-].[NH4+]>>[I:1][C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:5]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(I)c(I)n2CCN2CCCC2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(I)cn2CCN2CCCC2)CC1
Temperature: 0 °C
Yield: 98 %

Procedure:
Combine tert-butyl 4-(4,5-diiodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (51.00 g, 84.96 mmol) and 2-methyltetrahydrofuran (357 mL). Cool the reaction mixture to 0° C. Add 2 M isopropylmagnesium chloride in tetrahydrofuran (55.22 mL, 1.3 eq) dropwise over 45 minutes, maintaining the temperature below 5° C. Add saturated aqueous ammonium chloride. Separate the layers. Wash the aqueous phase with methyl tert-butyl ether. Wash the organics with aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, decolor with charcoal, filter, and concentrate in vacuo to give tert-butyl 4-(4-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate as a yellow solid (39.50 g, 98%). MS (ES) m/z=475 [M]+.
Reaction SMILES: [CH:1]([N:4]1[CH:13]([C:14](O)=[O:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]([N:4]1[CH:13]([CH2:14][OH:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1Cc2ccccc2CC1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1Cc2ccccc2CC1CO
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A sospension of N-isopropyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (8.0 g, 36 mmol) in tetrahydrofuran (100 ml) was slowly added to a refluxing suspension of lithium aluminum hydride (2.1 g, 54 mmol) in tetrahydrofuran (100 ml). The mixture was refluxed for two hours, then cooled at room temperature and treated with a mixture of tetrahydrofuran (7 ml) and water (0.9 ml), with 20% sodium hydroxide (2.3 ml) and finally with water (9.2 ml). The white solid was filtered off and the solvent was removed under reduced pressure yielding 5.0 g (yield 68%) of pure N-isopropyl-1,2,3,4-tetrahydroisoquinol-3-ylmethanol as thick oil. 1H-NMR δ7.12 (m, 4H), 4.54 (bs, 1H, exchange with D2O), 3.68 (s, 2H), 3.55-3.35 (m, 2H), 3.20-2.90 (m, 2H), 2.79 (d, 2H), 1.10 (d, 3H), 1.01 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([C@@H:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[O:36][CH3:37])[CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([N:26]3[CH2:27][CH2:28][C@@H:24]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:25]3)=[C:30]([O:36][CH3:37])[CH:31]=2)=[O:15])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: COc1cc(N)ccc1N1CC[C@@H](N2CCCC2)C1
Product: COc1cc(NC(=O)c2ccc(OCc3ccccc3)cc2C)ccc1N1CC[C@@H](N2CCCC2)C1

Procedure:
According to Method P, 4-benzyloxy-2-methyl-benzoic acid was reacted with (R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-methoxy-phenylamine. In this way the product was obtained with molecular weight 485.63 (C30H35N3O3); MS (ESI): 486 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[C:15]([F:18])=[C:14]([CH3:16])[O:13][N:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)[C@H]1CC[C@H](c2cc(C)on2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](c2noc(C)c2F)CC1
Temperature: 90 °C

Procedure:
A mixture of trans-4-(5-methyl-isoxazol-3-yl)-cyclohexanecarboxylic acid methyl ester (250 mg, 1.12 mmol) and Selectfluor® (476 mg, 1.34 mmol) in acetonitrile (5.6 ml) was heated at 90° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 50 ml-portions of ethyl acetate. The combined organic layers were washed with one 25 ml-portion of water/brine (1:1), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/tert-butyl methyl ether as eluent gave the title compound (35 mg, 13%) as light yellow oil. MS m/e: 241 ([M+H]+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:9]=1[CH:10]=[O:11].[N+:18]([CH3:21])([O-:20])=[O:19]>C1COCC1>[Cl:7][C:8]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:9]=1[CH:10]([OH:11])[CH2:21][N+:18]([O-:20])=[O:19]
Reactant: O=Cc1c(Cl)ccc(F)c1Cl
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
In a 3-necked 100 mL RBF, freshly ground potassium carbonate (0.486 g, 3.51 mmol) was added to a solution of 2,6-dichloro-3-fluorobenzaldehyde (2.26 g, 11.71 mmol) in THF (12 ml) at room temperature. Then nitromethane (8.88 ml, 164 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(2,6-dichloro-3-fluorophenyl)-2-nitroethanol (2.97 g, 11.69 mmol, 100% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.9, 4.8 Hz, 1H), 7.17 (dd, J=8.9, 7.8 Hz, 1H), 6.27 (m, 1H), 5.19 (dd, J=13.3, 10.1 Hz, 1H), 4.57 (dd, J=13.3, 3.4 Hz, 1H), 3.20 (br. s., 1H).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]1[CH:8]=CC=CC=1.C(N(C(C)C)CC)(C)C.BrCCC1[O:31][CH2:30][CH2:29][O:28]1.CC1CC=CCC=1>C(#N)C.C(Cl)Cl>[O:28]1[CH2:29][CH2:30][O:31][CH:8]1[CH2:3][CH2:2][NH:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: c1ccc(CNC2CCCC2)cc1
Reactant: BrCCC1OCCO1
Agent: CC1=CCC=CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C1CCC(NCCC2OCCO2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
To a suspension of N-benzylcyclopentanamine hydrochloride (0.986 g, 4.66 mmol) in acetonitrile (10 mL) was added di-iso-propylethylamine (2.0 mL, 11.5 mmol) and the mixture stirred at room temperature for 10 minutes. A solution of 2-(2-bromoethyl)-1,3-dioxolane (1.01 g, 5.58 mmol) in acetonitrile (5 mL) was added and the mixture heated at 80° C. for 48 hours. The reaction mixture was diluted with DCM and was washed with water, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was loaded onto an SCX-2 cartridge and eluted with acetonitrile (4 column volumes) and then 10% triethylamine/acetonitrile (4 column volumes). The product containing fractions were combined and the solvent evaporated at reduced pressure. The residue was dissolved in ethanol (10 mL) and 10% palladium on charcoal (0.90 g) added. The mixture was stirred at room temperature for 5 minutes and then 1-methyl-1,4-cyclohexadiene (1.9 mL, 16.9 mmol) added. The reaction mixture heated to reflux and then the reaction mixture stirred under reflux for 1 hour. The reaction mixture allowed to cool and the suspension filtered. The filtrate was evaporated at reduced pressure to afford the title compound (0.249 g, 40%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:29])[N:14]([CH3:28])[C:15]([C:24](OC)=[O:25])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].Cl>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]2[C:13](=[O:29])[N:14]([CH3:28])[C:15]([CH2:24][OH:25])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: Cn1c(CO)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Temperature: 90 °C
Reaction time: 5 h
Yield: 67.5 %

Procedure:
A solution of methyl 1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (6.4 g, 15.7 mmol) in Toluene (80 mL) was treated with LiBH4 (3.43 g, 157 mmol) and then heated at 90° C. overnight. Additional LiBH4 (3.43 g, 157 mmol) was added and the mixture was allowed to stir for an additional 5 hours at 90° C. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-100% ethyl acetate/hexanes) to afford 1-benzyl-4-(4-chlorophenyl)-5-(hydroxymethyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4.0 g, 10.6 mmol, 67% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 7.53-7.57 (m, 2H) 7.43-7.47 (m, 4H) 7.28-7.35 (m, 4H) 5.92-5.96 (m, 1H) 5.80 (s, 2H) 5.31 (s, 1H) 4.29-4.37 (m, 2H) 3.70 (s, 3H); LCMS (m/z) ES+=379 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F-].[K+].[SH:19][C:20]1[S:21][C:22]([CH3:25])=[N:23][N:24]=1>CN(C=O)C>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:15])[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:2]([S:19][C:20]1[S:21][C:22]([CH3:25])=[N:23][N:24]=1)=[N:3]2
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: Cc1nnc(S)s1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc(Sc2nc3cc(Cl)c(Cl)cc3nc2C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6,7-trichloro-3-isopropylquinoxaline (51 mg, 0.18 mmol) in DMF (4 ml) was added potassium fluoride 40% wt on alumina (80 mg, 0.55 mmol) followed by 2-mercapto-5-methyl-1,3,4-thiadiazole (26 mg, 0.20 mmol). The reaction mixture was stirred at room temperature overnight. The product was purified by flash column chromatography using ethyl acetate:hexanes 1:5 affording the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH:10](O)=[O:11]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: O=CO
Reactant: Nc1cc(F)cc(F)c1
Product: O=CNc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL) was heated to reflux for 4 h. The mixture was poured into ice-water and stirred for 0.5 h. The white solid was collected by filtration, and dried under vacuum to give 4.8 g (79%) of crude N-(3,5-difluorophenyl)formamide. To the solution of LiAlH4 (3.0 g, 78.9 mmol) in dry THF (50 mL) was added a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol) in dry THF (50 mL) at r.t. The mixture was stirred overnight and then quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml). The reaction mixture was filtered and extracted with EtOAc. Organics were dried (Na2SO4), and concentrated to give 3.8 g (86%) of the title compound as a pale brown oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@@H:51]([CH3:62])[CH2:50]3)[CH:43]=2)[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C1COCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:37]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@@H:51]([CH3:62])[CH2:50]6)[CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:27])[CH:29]=[CH:30][CH:31]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: C[C@H]1CN(Cc2cccc(-c3cccc(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (69 mg), 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (60 mg), HBTU (68 mg) and diisopropyl ethyl amine (112.5 μL) in DCM (5 mL) and THF (1 mL) were stirred at room temperature overnight. It was concentrated. Separation via CombiFlash then afforded the desired product (33 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]2[NH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[I:8].[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl.C(N(CC)C(C)C)(C)C.C(Cl)Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:11]2[N:12]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)c1ncc(-c2ccccc2)[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)c1ncc(-c2ccccc2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl [(1S)-2-(3-bromo-4-iodophenyl)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]carbamate (950 mg, 836 μmol), [β-(trimethylsilyl)ethoxy]methyl chloride (163 μL, 919 μmol), N,N-diisopropylethylamine (582 μL) and methylene chloride (8.91 mL) was stirred at 0° C. for 60 min and stirred at 25° C. for 2 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (432 mg, 59%). MF=C28H37BrIN3O3Si; LCMS found for C28H38BrIN3O3Si (M+H)+: m/z=698.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[Cl:12][C:11]1[C:2]([OH:1])=[CH:3][C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Oc1cc2c(cc1Cl)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a solution of 6-hydroxy-1,4-benzodioxane (1.52 g, 10 mmol) in N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.33 g, 10 mmol) at ambient temperature. The solution was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 30% gradient of ethyl acetate in hexanes to afford 7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (1.79 g, 96%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.02 (s, 1H), 6.83 (s, 1H), 6.56 (s, 1H), 4.27-4.16 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1Cl>>[N+:13]([C:8]1[CH:9]=[CH:10][C:11]([NH:3][CH2:2][CH2:1][NH2:4])=[C:6]([Cl:5])[CH:7]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: NCCN
Product: NCCNc1ccc([N+](=O)[O-])cc1Cl

Procedure:
Ethylene diamine is reacted with 3,4-dichloronitrobenzene to form 4-nitro-2-chloro-N-(β-aminoethyl) aniline, which is reacted in an acetic solution with potassium isocyanate to form 4-nitro-2-chloro-N-(β-ureidoethyl) aniline. This latter compound is reduced with hydrazine in the presence of Raney's nickel, yielding 4-amino-2-chloro-N-(β-ureidoethyl) aniline.
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([NH:30][C@H:31]3[CH2:35][CH2:34]N[CH2:32]3)=[O:29])[CH2:11]2)=CC=1.[N+:38]([C:41]1[CH:54]=[CH:53][C:44]([CH2:45][O:46][C:47]([NH:49][C:50](=[NH:52])[CH3:51])=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([C:28]([NH:30][C@H:31]2[CH2:35][CH2:34][N:52]([C:50](=[N:49][C:47]([O:46][CH2:45][C:44]3[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:54][CH:53]=3)=[O:48])[CH3:51])[CH2:32]2)=[O:29])[CH2:11]1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 53.3 %

Procedure:
Following a procedure similar to that described in Preparations 23(iii) and 23(iv), but using 1.08 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-pyrrolidin-3-ylaminocarbonyl)pyrrolidine hydrochloride and 440 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine, 608 mg of the title compound were obtained as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11](NCC#N)=[O:12])=[CH:4][CH:3]=1.BrC(CC(C)C)[C:29](OC)=[O:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([O:30][CH3:29])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: CC(C)CC(OC(c1ccncc1)c1ccc(Br)cc1)C(=O)NCC#N
Product: COC(=O)C(CC(C)C)OC(c1ccncc1)c1ccc(Br)cc1

Procedure:
Using the same protocol as described in example 23, step 2, (4-bromophenyl)(pyridin-4-yl)methanol from step 1 (594 mg, 2.20 mmol) was added to methyl 2-bromo-4-methylpentanoate (377 μL, 2.31 mmol). The crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12].[F-].[K+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([C:2]2[C:9]([CH3:10])=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Cc1ccc(C#N)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOc1cccc(-c2cc(C#N)ccc2C)c1
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of 3-chloro-4-methylbenzonitrile (3.03 g, 20 mmol), 3-ethoxyphenylboronic acid (4.98 g, 30 mmol), palladium acetate (74 mg, 0.4 mmol), 2-dicyclohexylphosphanyl-biphenyl (0.210 g, 0.6 mmol), and KF (3.48 g, 60 mmol) in THF (25 mL) at room temperature was stirred for 12 hours and concentrated. The concentrate was dissolved in ethyl acetate (10 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexanes to provide 4.68 g (99%) of the desired product. MS (DCI/NH3) m/z 255 (M+NH4)+; 1H NMR (CDCl3) δ 7.54-7.51 (m, 2H), 7.36-7.31 (m, 2H), 6.93 (m, 1H), 6.85-6.78 (m, 2H), 4.07 (q, 2H), 2.32 (s, 3H), 1.34 (t, 3H).