Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][C:25]([CH3:27])=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35].CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:37][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][C:25]([CH3:27])=[N:26][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1=NC2=Cn3c(cc4c(C5CCCCC5)cccc43)-c3cc(C(=O)O)ccc3N2C1
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC1=NC2=Cn3c(cc4c(C5CCCCC5)cccc43)-c3cc(C(=O)NS(=O)(=O)N(C)C)ccc3N2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
To a solution of 10-cyclohexyl-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (58 g, 0.14 mmol) and N,N-dimethylsulfamide (82 g, 0.66 mol) in DMF (2 mL) added DMAP (80 mg, 0.66 mmol) and then EDCI-HCl (100 mg, 0.52 mmol). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxamide (32 mg, 0.062 mmol, 44%) as a pink solid. 1H NMR (300 MHz, CD3OD) δ 1.14-1.32 (m, 1H), 1.36-1.57 (m, 3H), 1.73-1.85 (m, 2H), 1.94-2.20 (m, 4H), 2.34 (s, 3H), 2.84-2.98 (m, 1H), 3.04 (s, 6H), 5.20 (d, J=16.1 Hz, 1H), 5.97 (d, J=16.1 Hz, 1H), 7.66 (dd, J=8.6, 1.7 Hz, 1H), 7.71 (s, 1H), 7.77-7.90 (m, 4H), 8.01 (d, J=8.8 Hz, 1H), 8.27 (s, 1H). LCMS: m/e 518 (M+H)+, ret time 1.80 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N:20]=[C:21]=[O:22])=[CH:15][C:14]=2[Cl:23])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[C:27]([N:29]=[C:30]=[O:31])=[O:28]>CCCCCCC>[Cl:1][C:2]1[C:3]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N:20]3[C:21](=[O:22])[O:28][C:27]([C:26]4[C:25]([F:24])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])=[N:29][C:30]3=[O:31])=[CH:15][C:14]=2[Cl:23])=[N:4][CH:5]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:7]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: O=C=Nc1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Solvent: CCCCCCC
Product: O=c1nc(-c2c(F)cccc2F)oc(=O)n1-c1cc(Cl)c(Oc2ncc(OC(F)F)cc2Cl)c(Cl)c1
Yield: 86 %

Procedure:
0.8 g (2.2 mmol) of 4-(3-chloro-5-difluoromethoxy-2-pyridyloxy)-3,5-dichlorophenyl isocyanate and 0.4 g (2.2 mmol) of 2,6-difluorobenzoyl isocyanate were stirred for 16 hours at 70° C. with the exclusion of moisture, and, after cooling, the solid formed was stirred with 5 ml of absolute n-heptane, filtered off under suction and recrystallized from cyclohexene/toluene; melting point 154°-6° C., yield: 86%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][CH:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]3[CH2:21][CH2:20][CH2:19][O:18]3)=[O:14])=[CH:11][C:6]=2[N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:1][NH:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][CH:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]3[CH2:21][CH2:20][CH2:19][O:18]3)=[O:14])=[CH:11][C:6]=2[NH:5][N:4]=1
Reactant: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)NC(c3ccccc3)C3CCCO3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CNc1n[nH]c2cc(NC(=O)NC(c3ccccc3)C3CCCO3)ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(phenyl(tetrahydrofuran-2-yl)methyl)urea (320 mg, 0.526 mmol) was taken up in TFA (3.0 ml). Triethylsilane (0.126 ml, 0.789 mmol) was added and the reaction was allowed to stir at rt for 30 mins. The reaction mixture was concentrated in vacuo. Saturated NaHCO3 was slowly added. The products were then washed with EtOAc (3×). The combined organic layers were then washed with brine, dried over MgSO4, filtered through celite, then concentrated in vacuo. The oil was taken up in 2 ml of DCM and loaded directly onto silica gel. Purification by MPLC 0-15% EtOAc/MeOH gave 1-(3-(methylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(phenyl(tetrahydrofuran-2-yl)methyl)urea. MS ESI calc'd. for C19H23N6O2 [M+H]+ 367. found 367.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[C:33]([CH2:34][NH2:35])=[CH:32][C:31]([C:36]([F:39])([F:38])[F:37])=[N:30]1>C(Cl)Cl.O>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[C:33]([CH2:34][NH:35][C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[C:2]([F:1])[CH:3]=2)=[O:19])=[CH:32][C:31]([C:36]([F:38])([F:39])[F:37])=[N:30]1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl)Nc1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (0.175 g, 0.63 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.25 mL, 1.9 mmol, 3.0 eq.) followed by compound (1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.218 mg, 0.63 mmol, 1.0 eq.) at RT and stirred for 16 h at RT. The reaction mixture was diluted with water (10 mL) and extracted into DCM (25 mL). The organic layer was washed with brine (10 mL), dried over (Na2SO4) and the solvent evaporated under vacuum. The resulting residue was purified by CC using EtOAc/PE (1:1) as eluent to get 1-((1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (70 mg; 23%) as white solid (TLC system: EtOAc, Rf: 0.55).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:31])[CH2:14][C:15]([O:17][CH:18]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:19])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:31])[CH2:14][C:15]([O:17][CH:18]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH3:19])=[O:16]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)CC(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)CC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (900 mg, 6 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 3-methylbutanoate (800 mg, 2.8 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 19 (200 mg, 21% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.88-0.97 (m, 8H), 1.22-1.38 (br. m, 3H), 1.42 (d, J=5.2 Hz, 3H), 1.71-1.74 (m, 2H), 1.90-2.02 (br. m, 3H), 2.1-2.2 (br. m, 3H), 2.85 (t, J=6.4 Hz, 2H), 6.69 (q, J=5.6 Hz, 1H), 7.48 (t, J=6.0 Hz, 1H), 12.01 (br. s, 1H). MS (ESI) m/z 352.15 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1.CCCCCCCCCCCC>C(OCC)(=O)C.COCCOC>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:26][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(S)c1
Reactant: COC(=O)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cccc(Sc2cccc(OC)c2)c1
Temperature: 80 °C
Reaction time: 22 h
Yield: 80.2 %

Procedure:
Cu(I) iodide (10 mg, 0.05 mmol), potassium carbonate (276 mg, 2.0 mmol) and Methyl 3-iodobenzoate (276 mg, 1.0 mmol) were charged into a screw-capped test tube with Teflon-lining. The tube was evacuated and backfilled with argon (3 cycles). Anhydrous DME (1.0 mL) and 3-methoxythiophenol (124 μL, 1.0 mmol) were added by syringes at room temperature. The tube was heated to 80° C. and stirred for 22 hours. The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added. The aliquot was analyzed GC. The reaction mixture was then filtered and concentrated. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate=20/1 to afford colorless liquid as the titled product (220 mg, 81% yield). Rf=0.5 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 8.02-8.03 (m, 1 H), 7.89 (dt, 1 H, J=1.2 Hz, 8.1 Hz), 7.45-7.49 (m, 1 H), 7.34 (t, 1 H, J=7.5 Hz), 7.21 (t, 1 H, J=8.1 Hz), 6.86-6.92 (m, 2 H), 6.79 (ddd, 1 H, J=0.6 Hz, 2.4 Hz, 8.1 Hz), 4.34 (q, 2 H, J=7.2 Hz), 3.76 (s, 3 H), 1.37 (t, 3 H, J=7.2 Hz). 13C NMR (CDCl3, 75 MHz) δ 166.0, 160.2, 136.5, 136.3, 135.2, 132.0, 131.7, 130.3, 129.3, 128.4, 123.7, 116.6, 113.5, 61.5, 55.7, 14.7. IR (neat, cm−1) 3064, 2981, 2960, 2937, 2360, 2342, 1717. MS (EI) m/z (relative intensity) 288 (100), 243 (30). Anal. Cald. for C16H16O3S, Cald. C: 66.64, H: 5.59; Found C: 66.87, H: 5.66.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C:9]1[N:10]([CH3:38])[C:11](=[O:37])[C:12]2([N:36]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[CH:20]=1)[S:15][CH:14]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13]2>CO.O>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[NH2:8][C:9]1[N:10]([CH3:38])[C:11](=[O:37])[C:12]2([N:36]=1)[C:21]1[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[CH:20]=1)[S:15](=[O:1])[CH:14]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:13]2
Reactant: CN1C(=O)C2(CC(c3ccccc3)Sc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2(CC(c3ccccc3)S(=O)c3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.4 %

Procedure:
To a solution of 3-(2-amino-1-methyl-5-oxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile TFA salt (27 mg, 0.05 mmol) in MeOH (5 mL) and H2O (0.1 mL) is added NaIO4 (21.4 mg, 0.10 mmol). The resulting mixture is stirred overnight at rt, then purified by preparative HPLC to give 3-(2-amino-1-methyl-1′,5-dioxo-2′-phenyl-1,5-dihydrospiro[imidazole-4,4′-thiochroman]-6′-yl)benzonitrile TFA salt (16 mg) with 5 mg of recovered starting material. MS ESI +ve m/z 441 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:20][CH3:21]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:4]2[C:3]3[C:2]([C:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:12]=[CH:13]1
Reactant: CCCOc1ccc(B(O)O)cc1
Reactant: CC(C)Cn1cnc2cnc3cccc(Br)c3c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2cccc3ncc4ncn(CC(C)C)c4c23)cc1
Yield: 90 %

Procedure:
9-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (1.0 g, 3.4 mmol) and 4-propoxyphenylboronic acid (1.0 g, 5.5 mmol) were coupled according to Part J of Example 1. The palladium (II) acetate (2.5 mg, 0.011 mmol) was added as a 5 mg/mL solution in toluene. The work-up procedure described in Parts 125–135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 1.1 g of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline as a dark brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:35][C:36]([F:53])([F:52])[C:37]1[N:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:36]([F:35])([F:52])[F:53])[N:42]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)n2)OC1(C)C
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C(F)(F)F)n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 1g (1.09 mg, 2.13 mmol) in dimethoxyethane (15 ml), was added 6-(Trifluoromethyl)pyridine-2-boronic acid pinacol ester (750 mg, 2.56 mmol), and 2M Na2CO3 (2.1 mL, 4.26 mmol). The mixture was degassed, tetrakis(triphenylphosphine)palladium (0) (490 mg, 0.426 mmol) was added and the mixture was degassed, and then heated to 80° C. After 1 hr, the reaction was cooled to room temperature, diluted with EtOAc and washed with NaHCO3 and brine. Purification by column chromatography gave the title compound (987 mg, 91%). Calcd for C27H25F6NO2 (M+H) 509.44, Found 510.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:20])[N:8]([C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>C(O)(C)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:20])[N:8]([C:12]3[CH:17]=[C:16]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[N:15]=[C:14]([NH2:19])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(Cl)nc(N)n1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CC(C)(C)O
Product: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-chloropyrimidin-2-amine (2.3 g, 6.5 mmol) and 1-methyl piperazine (3.61 mL, 32.6 mmol) in tert-butyl alcohol (10 mL) and was heated at 120° C. for 20 h. The reaction mixture was cooled to r.t., poured into water, extracted with AcOEt, washed with sat'd NaHCO3 aqueous solution and brine, dried with MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 10% methanol in methylene chloride to afford the desired compound. LCMS (M+H)+: m/z=417.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:19][C:20]2[CH:30]=[CH:29][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1cccc(C(=O)OCC)c1
Yield: 49.8 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-methylthiobutanoic acid (2.99 g) and ethyl 3-aminobenzoate (1.34 g) were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.01 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-4-methylthiobutanamide (2.018 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2cc(Br)cc(COCC3(c4ccccc4)CCNCC3)c2)cc1

Procedure:
tert-Butyl 4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (24.3 mg, 0.04 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the compound purified by column chromatography (10% ammonia in methanol/methylene chloride) to afford 13.2 mg (72%). 1H-NMR (CDCl3, 500 MHz) δ 7.71-7.73 (m, 2H), 7.31-7.37 (m, 5H), 7.28 (s, 1H), 7.20-7.22 (m, 2H), 4.38 (s, 2H), 3.44 (s, 2H), 2.91-2.94 (m, 2H), 2.74-2.78 (m, 2H), 2.16-2.20 (m, 2H), 1.89-1.93 (m, 2H). Mass spec.: 463.09 (MH)+. Accurate mass spec.: m/z 463.1205 [MH]+, Δ=1.0 ppm.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])(O)O>>[F:12][C:8]1[C:7]([OH:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])=[N:3]2
Reactant: Oc1ccc2nc(Cl)ccc2c1F
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Product: Cc1cc(C(=O)O)ccc1-c1ccc2c(F)c(O)ccc2n1

Procedure:
Followed the procedure described for Example 70, starting from 2-chloro-5-fluoroquinolin-6-ol (Intermediate 16) and 4-borono-3-methylbenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.03 (b, 1H), 10.47 (b, 1H), 8.43 (d, 1H), 7.93 (s, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.52 (t, 1H), 2.43 (s, 3H). MS (ESI): m/z=296.38 [M−H]−.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].P(=O)(O)(O)O.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][CH3:13].[CH2:18](O)[CH3:19]>>[CH2:16]([O:15][C:11](=[O:14])[CH:12]([CH3:1])[CH2:13][CH:18]=[CH2:19])[CH3:17]
Reactant: CCO
Reactant: O=C([O-])O
Reactant: CCOC(=O)CC
Agent: O=P(O)(O)O
Agent: [Na+]
Product: C=CCC(C)C(=O)OCC

Procedure:
The autoclave is then opened and 12.6 g sodium bicarbonate is added to the reaction mass in order to neutralize the phosphoric acid. 30 g Primol (a registered trademark for mineral oil manufactured by the Exxon Co. of Linden, N.J.) is then added as a still base, and the reaction mass is fractionally distilled on a 1 × 20 inches packed Goodloe distillation column (i) at atmospheric pressure and 129°C (yielding a mixture of ethanol and ethyl propionate (245 g) and (ii) at 40 mm Hg. pressure and 75°C (yielding 264 g of ethyl-2-methyl-4-pentenoate. Yield, based on triethyl orthopropionate used, 73.5%.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:6][NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1

Procedure:
A solution of trans-methyl[4-(1-oxo-1,2-dihydroisoquinolin-6-yloxy)cyclohexyl]-carbamic acid tert-butyl ester (400 mg, 1.07 mmol) in dichloromethane (9 ml) and trifluoroacetic acid (1 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo then purified by ion exchange chromatography to give trans-6-(4-methylaminocyclohexyloxy)-2H-isoquinolin-1-one, EI-MS: m/z=273.4 [M+H]+.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C@@H:14]([OH:23])[C@@H:15]([OH:22])[C@H:16]([OH:21])[C@H:17]([OH:20])[CH:18]=[O:19])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]>C(O)[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>[CH2:10]([OH:11])[C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@@H:14]([OH:23])[C@@H:15]([OH:22])[C@H:16]([OH:21])[C@H:17]([OH:20])[CH2:18][OH:19])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7].[CH2:10]([OH:11])[C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@@H:14]([OH:23])[C@@H:15]([OH:22])[C@H:16]([OH:21])[C@@H:17]([OH:20])[CH2:18][OH:19])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7].[CH2:10]([OH:11])[C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@@H:14]([OH:23])[C@@H:15]([OH:22])[C@H:16]([OH:21])[C@@H:17]([OH:20])[CH2:18][OH:19])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: OC[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
In the process according to the invention, the depletion of the epimerized mixture in isomaltose is, on the contrary, carried out in such a manner as to obtain a fraction containing a roughly equimolecular proportion of isomaltose and α-D-glucopyranosyl-(1→6)-D-mannose, the other fraction being constituted by very pure isomaltose. By roughly equimolecular is meant from 40 to 60% and more preferably from 45 to 55% of one of the two compounds relative to the total mass of the two compounds. This way of proceeding has the advantage of directly obtaining a mixture which after hydrogenation will provide the two components of palatinitol, namely isomaltitol and GPM in roughly equimolecular proportions, without having to resort to remixing pure fractions.
Reaction SMILES: [CH2:1]([NH:9][S:10]([N:13]1[CH2:20][CH2:19][N:18]([C:21]2[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:17][C:14]21[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C>[CH2:1]([N:9]([CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[S:10]([N:13]1[CH2:20][CH2:19][N:18]([C:21]2[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:17][C:14]21[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(NCCc1ccccc1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S(=O)(N(CCCc1ccccc1)CCc1ccccc1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaza-spiro[2.5]octane-4-sulfonic acid phenethyl-amide (intermediate 5) (0.05 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.05 mmol) and (3-bromo-propyl)-benzene (0.05 mmol). Stirred at rt for 2 h and then filtered through a syringe filter (0.45 μm). The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.