Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:11])[NH:9][OH:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:20][C:19]=1[O:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:14])=[O:13].[CH2:39](O)[CH2:40][CH2:41][CH3:42].[ClH:44]>>[ClH:44].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:11])[NH:9][OH:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:20][C:19]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:37])(=[O:13])=[O:14]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)NO)ccc2O)c(OCC(=O)O)c1
Reactant: CCCCO
Agent: Cl
Product: CCCCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)NO)ccc1O

Procedure:
Method 2) A solution of 110 g of [4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid in 1.00 L of 14% hydrogen chloride n-butanol solution was stirred at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give 111 g of crude crystal. The crude crystal was recrystallized from n-butanol-diisopropyl ether to give 83.3 g of n-butyl [4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:20][CH2:21][CH2:22][CH3:23])=[N:15][CH:16]=[C:17](I)[CH:18]=3)=[N:8][C:7]=12)[CH3:2].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].C(#N)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:3]1[N:4]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:20][CH2:21][CH2:22][CH3:23])=[N:15][CH:16]=[C:17]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[CH:18]=3)=[N:8][C:7]=12)[CH3:2]
Reactant: CCCOc1ncc(I)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Reaction time: 2 h

Procedure:
The product from stage e) (0.25 mmol) was suspended in triethylamine (2 ml) and trimethylsilylacetylene (0.39 mmol) and acetonitrile (2 ml to try and solubilise reactants). Pd(PPh3)2Cl2 (0.006 mmol) and cuprous iodide (0.006 mmol) were added and the reaction mixture stirred. After 1 h a further portion of trimethylsilylacetylene (0.19 mmol) was added and stirring continued for 2 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organics were washed with brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 99% dichloromethane/methanol) gave the title compound; 1H NMR (400MHz, MeOD): δ=0.25 (s, 9H), 1.05 (t, 3H), 1.31 (t, 3H), 1.44 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q, 2H), 4.33 (t, 2H), 4.52 (t, 2H), 4.54-4.80 (m, 2H), 5.18-5.25 (m, 1H), 8.32 (d, 1H), 8.74 (d, 1H); LRMS (TSP—positive ion) 569 (MNH4+), 452.0 (MH+); Anal. Found C, 60.82;H, 6.90; N, 15.15 Calcd for C28H38O4N6Si: C, 61.07;H, 6.95; N, 15.26.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][NH:12][C:13]1[NH:23][C:22]2[C:15](=[C:16]([CH2:24][C:25]3[CH:30]=[C:29]([Br:31])[C:28]([O:32][CH3:33])=[C:27]([Br:34])[CH:26]=3)[C:17]([N:19]=[CH:20][CH:21]=2)=[O:18])[N:14]=1.I[CH3:36]>CN(C=O)C.C1COCC1>[CH3:11][NH:12][C:13]1[N:23]=[C:22]2[C:15](=[C:16]([CH2:24][C:25]3[CH:26]=[C:27]([Br:34])[C:28]([O:32][CH3:33])=[C:29]([Br:31])[CH:30]=3)[C:17]([N:19]([CH3:36])[CH:20]=[CH:21]2)=[O:18])[N:14]=1
Reactant: CI
Reactant: CNc1nc2c(Cc3cc(Br)c(OC)c(Br)c3)c(=O)nccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1nc2ccn(C)c(=O)c(Cc3cc(Br)c(OC)c(Br)c3)c-2n1
Temperature: -78 °C
Yield: 43.6 %

Procedure:
Sodium bis(trimethylsilyl)amide (1 M in THF, 24 μL, 0.0240 mmol) was added dropwise to a solution of ceratamine B from Example 12 (formula (IIIB); R1=methyl) (12.1 mg, 0.0266 mmol) in DMF:THF (1:1, 0.27 mL) at 0° C. The reaction mixture was cooled to −78° C. and iodomethane (2.1 μL, 0.0346 mmol) was added dropwise followed by warming to −10° C. The reaction was quenched by the addition H2O (2 mL), and was extracted with EtOAc (6×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to afford crude ceratamine A (formula (IIIA); R1=methyl). Purification by flash chromatography (C-18 reverse-phase silica, 70% MeOH:H2O) yielded pure ceratamine A (formula (IIIA); R1=methyl) (5.4 mg, 0.0116 mmol, 43%) as a yellow solid. The major tautomer was characterized: 1H NMR (400 MHz, DMSO) δ 8.68 (m, NH), 7.74 (d, J=9.9 Hz, 1H), 7.66 (s, 2H), 6.42 (d, J=9.9 Hz, 1H), 4.23 (s, 2H), 3.72 (s, 3H), 3.55 (s, 3H), 3.07 (d, J=4.9 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 175.6, 169.7, 164.1, 160.5, 151.4, 142.9, 140.2, 133.1, 121.3, 116.6, 100.4, 60.3, 43.7, 35.0, 29.2; HRMS (ESI) m/z calcd for C17H17Br2N4O2: 466.9713. found: 466.9701. These data from synthetic ceratamine A are consistent with data reported for natural products.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:28]3[CH2:33][CH2:32][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]3)[CH2:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=3[F:27])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH3:40][C:41]1[C:46]([C:47]([OH:49])=O)=[C:45]([CH3:50])[N:44]=[CH:43][N:42]=1>>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([F:27])=[C:19]([CH:24]=1)[CH2:18][N:17]([CH:28]1[CH2:29][CH2:30][N:31]([CH:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:47]([C:46]2[C:41]([CH3:40])=[N:42][CH:43]=[N:44][C:45]=2[CH3:50])=[O:49])[CH2:32][CH2:33]1)[C:14]1[CH:13]=[CH:12][C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][CH:8]=2)=[CH:16][CH:15]=1)#[N:26]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: COC(=O)c1ccc(Oc2ccc(N(Cc3cc(C#N)ccc3F)C3CCN(C(C)CCN)CC3)cc2)cc1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
Using general procedure E with the above amine (90 mg, 0.17 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (29 mg, 0.19 mmol) and then using general procedure K with the resulting ester afforded COMPOUND 228 as a white solid (40 mg, 36% over 2 steps). 1H NMR (CDCl3) δ 1.14-1.26 (m, 3H), 1.67-2.19 (m, 4H), 2.40-2.59 (m, 1H), 2.48 (s, 6H), 2.73-2.85 (m, 1H), 3.01-3.17 (m, 3H), 3.32-3.36 (m, 2H), 3.38-3.51 (m, 1H), 3.58-3.75 (m, 2H), 4.20-4.35 (m, 2H), 6.69 (d, 2H, J=8.4 Hz), 6.82-6.92 (m, 4H), 7.10-7.18 (m, 1H), 7.49-7.61 (m, 2H), 7.71 (d, 2H, J=7.8 Hz), 8.41 (br s, 1H), 8.87 (s, 1H). 13C NMR (CDCl3) δ 12.80, 22.42, 27.60, 28.02, 32.11, 38.06, 44.46, 51.32, 53.84, 56.22, 58.67, 108.95, 116.92, 117.30, 118.65, 121.60, 127.77, 129.38 (d, J=15 Hz), 130.85, 131.82, 133.35, 144.82, 148.94, 157.73, 161.83, 163.01 (d, J=256 Hz), 163.50, 167.60, 171.81. ES-MS m/z 651 (M+H). Anal. Calcd. for C37H39N6O4F.1.1CH2Cl2: C, 61.49; H, 5.58; N, 11.29; F, 2.55. Found: C, 61.44; H, 5.70; N, 11.14; F, 2.38.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[CH:3]=[C:2]([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[N:40][CH:41]=2)[CH:10]=[C:9]2[C:5]=1[C:6]([CH3:14])=[N:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (400 mg, 0.928 mmol) in DMF (20 mL) was added tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (397 mg, 1.02 mmol) followed by sodium carbonate (246 mg, 2.32 mmol) dissolved in water (4 mL) and degassed with argon for 30 min. PdCl2(PPh3)2 (65 mg, 0.092 mmol) was added and the mixture again degassed with argon for 10 min. The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (650 mg). The crude compound was purified by silica gel chromatography (eluent: 0-10% MeOH: DCM). The product was triturated with diethyl ether (150 mL) to afford the title compound as an off white solid (270 mg, 47%). 1H NMR (DMSO-d6, 400 MHz): δ 1.498 (s, 9H), 1.560 (d, J=6.4 Hz, 6H), 2.128 (s, 3H), 2.413 (s, 3H), 2.526 (s, 3H), 3.579 (s, 8H), 4.610 (d, J=5.6 Hz, 2H), 4.760-4.824 (m, 1H), 5.907 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 7.311-7.346 (m, 2H), 7.454 (s, 1H), 7.735 (d, J=8.8 Hz, 1H), 8.463 (s, 1H), 10.991 (brs, 1H). LCMS (ES+): 614.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:39][C:35]4[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=4)[CH2:29][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Reactant: Cn1ccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(Cc4nccn4C)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture 3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.045 g, 0.0001 mol), 1-methyl-2-imidazole carboxaldehyde (0.011 g, 0.00011 mol), and acetic acid (0.018 g, 0.0003 mol) in dichloroethane (4 mL) was stirred at room temperature under an atmosphere of nitrogen for 1.5 hrs. Sodium triacetoxyborohydride (0.064 g, 0.0003 mol) was added into the mixture and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction was quenched with an aqueous 5 N solution of sodium hydroxide. The solvents were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with water and brine. The solvents were removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-{1-[(1-methyl-1H-2-imidazolyl)methyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.03 g, 0.00006 mol).
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:21]12CC(C=C1)C=[CH:22]2.CCN(CC)CC>C1(C)C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:22]=[CH:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: C1=CC2C=CC1C2
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 70 °C
Yield: 78.5 %

Procedure:
A stirred mixture of hydrazonoyl chloride 65 (1.55 g, 4.99 mmol), bicyclo[2.2.1]hepta-2,5-diene (1.25 mL, 24.6 mmol) and Et3N (2.0 mL, 14.3 mmol) in toluene (10 mL) was heated to 70° C. for 1 h. The mixture was cooled and filtered, the filter cake was washed with toluene (10 mL) and the organic fractions were combined and evaporated. The residue was refluxed in xylenes (30 mL) for 2 h. Column chromatography on silica gel, eluting with hexanes, firstly gave xylenes, and then further elution with CH2Cl2 gave ethyl 1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole-3-carboxylate (66) (1.176 g, 79%) as a white solid: mp 76-78° C.; 1H NMR (CDCl3) δ 7.91 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.00 (d, J=2.5 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). APCI MS m/z 301 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:17])[CH2:7][C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11][CH3:12])[CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:17][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:13]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])=[C:10]([O:11][CH3:12])[CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCO)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CCOS(C)(=O)=O)ccc1OS(C)(=O)=O
Temperature: 25 °C
Yield: 86.6 %

Procedure:
44 g (0.39 mole) methanesulfonyl chloride was slowly added to a solution of 30 g (0.178 mole) homovanillyl alcohol and 45.3 g (0.45 mmole) triethylamine in 500 ml dichloromethane at −10° C. After stirring at room temperature over night the salts were filtered off, the organic phase was washed with sodium bicarbonate and brine, dried (magnesium sulfate) and evaporated in vacuo to give 50 g (yield 86%) of 3-methoxy-4-(methylsulfonyloxy)phenethyl methanesulfonate.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([CH3:32])=[CH2:31])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])[C:6](=[O:8])[O-:7])(C)C>CO.[Pd]>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[N:17]=[CH:16][C:15]([NH:14][C:12]([C@H:9]([NH:5][C:6](=[O:8])[O:7][C:24]([CH3:30])([CH3:25])[CH3:23])[CH2:10][CH3:11])=[O:13])=[CH:20][CH:19]=2)=[CH:23][C:24]=1[CH:30]([CH3:31])[CH3:32])#[N:29]
Reactant: C=C(C)c1cc(Oc2ccc(NC(=O)[C@@H](CC)N(C(=O)[O-])C(C)(C)C)cn2)ccc1C#N
Agent: [Pd]
Solvent: CO
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl((1R)-1-{[(6-{[4-cyano-3-(1-methylethenyl)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 178, 73 mg) in MeOH (10 mL) was added Pd 10% w/w on activated carbon (14 mg) and the reaction mixture was stirred for 30 minutes under H2 atmosphere (P=1 atm). The catalyst was filtered off and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel (SNAP 10 g) eluting from 75:25 to 40:60 cyclohexane/ethyl acetate affording the title compound (62 mg) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC1C=CC(S(O[CH2:23][CH2:24][CH2:25][NH:26][C:27]2[C:28](=[O:44])[N:29]([C:40]([CH3:43])([CH3:42])[CH3:41])[S:30](=[O:39])(=[O:38])[C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=O)=O)=CC=1>>[C:40]([N:29]1[C:28](=[O:44])[C:27]([NH:26][CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[C:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:30]1(=[O:38])=[O:39])([CH3:41])([CH3:42])[CH3:43]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: COC(=O)c1cccc(O)c1
Product: COC(=O)c1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Yield: 54 %

Procedure:
The title compound was prepared as described for Example 12 from methyl 3-hydroxybenzoate and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the residue purified by silica gel column chromatography (Horizons Biotage) using DCM as eluent to give the title compound (0.077 g, 54%). 1H NMR (500 MHz CDCl3): δ 7.66 (d, 1H), 7.54-7.48 (m, 3H), 4.47-7.42 (m, 3H), 7.36 (t, 1H), 7.07 (dd, 1H), 5.70 (t, 1H), 3.94-3.90 (m, 5H), 3.13-3.08 (m, 2H), 1.90-1.84 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 167.1, 159.8, 158.5, 135.3, 131.8, 131.7, 129.8, 129.7, 128.8, 125.3, 122.6, 120.2, 114.6, 107.3, 66.2, 61.7, 52.4, 42.3, 28.9, 27.8; Mass Spectrum M+H+ 473.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[CH3:36][CH:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:38]=O.O>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]=[CH:36][CH:37]([CH3:38])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:29][CH:30]=1
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)C=CCc1ccc(OC)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
p-Methoxyphenethyltriphenylphosphonium bromide (3.40 g, 7.12 mmol, 1.0 equiv.) in THF (14 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 4.5 mL, 7.12 mmol, 1.0 equiv.) at 0° C., the red solution was stirred at 65° C. for 1 h. The mixture was re-cooled to 0° C., 2-methylundecanal (1.97 g, 10.7 mmol, 1.5 equiv.) in THF (6 mL) was added, and the mixture was stirred at 70° C. for 14 h. After addition of H2O, the aqueous layer was extracted with cyclohexane (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 98:2) to yield 1.36 g (63%) of the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Cl:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:10])[N:11]=[CH:12][NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1ncc(Cl)cc1N
Product: O=c1nc[nH]c2cc(Cl)cnc12
Temperature: 155 °C
Reaction time: 22 h
Yield: 88.5 %

Procedure:
A suspension of 3-amino-5-chloropicolinamide (1.1 g, 6.41 mmol) in triethyl orthoformate (15.99 mL, 96 mmol) was stirred at 155° C. for 22 hours. After cooling to RT, the yellow precipitate was collected by vacuum filtration and washed with hexanes to yield the title intermediate (1.03 g, 5.67 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (s, 1 H) 8.27 (d, J=2.35 Hz, 1 H) 8.80 (d, J=2.25 Hz, 1 H) 12.68 (br. s., 1 H). LC/MS (ESI+) m/z=182 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]1[N:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)C(OCC)=O)[CH3:2].[Cl-].[Na+].CS(C)=O>O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:11]1[N:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Cl)nn1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-(6-chloro-pyridazin-3-yl)-malonic acid diethyl ester (from step 1, ca. 65%, 19.0 g), sodium chloride (11.8 g), water (1.3 mL), and dimethyl sulfoxide (80 mL) was stirred at 150° C. for 4.5 h. More sodium chloride (5.0 g) and water (0.6 mL) were then added and stirring was continued at 160° C. for another 2 h. After cooling to room temperature, water was added and the resulting mixture was extracted with tert-butyl methyl ether. The combined extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated to give the crude title compound that was submitted to the next reaction step without further purification. Yield: 9.0 g (64% of theory); LC (method 1): tR=1.18 min.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.CC(C)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[OH:12][C:2]1([CH3:1])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(O)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(O)CCC(=O)CC1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (1 equiv) in a 2:1 mixture of acetone and water (0.38 M) was added pyridinium p-toluenesulfonate (0.2 equiv). The resulting mixture was refluxed for 8 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound (86% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 3.96-3.93 (m, 2H), 2.27-2.25 (m, 1H), 2.25-2.22 (m, 1H), 2.01-1.94 (m, 2H), 1.90-1.82 (m, 2H), 1.38 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH:7]([CH3:10])[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27](=[O:30])[CH2:28][NH:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:12])[CH3:11])[CH3:10])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(CN)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CNCC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2-(tert-Butyl-dimethyl-silanyloxy)-propylamine (6.0 g, 31.6 mmol) was dissolved in DMF (60 mL). Diisopropylethylamine (5.5 mL, 31.6 mmol) and bromo-acetic acid tert-butyl ester (3.6 g, 18.6 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h. The mixture was evaporated onto silica gel and and purified by column chromatography using a gradient, starting eluting with ethyl acetate/heptane 20:80 up to ethyl acetate/heptane 80:20. The product was isolated as an oil. Yield: 4.0 g, 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH3:23])[C:14]=1[OH:24]>C([O-])([O-])=O.[K+].[K+].COCCOC.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH3:23])[C:14]=1[OH:24]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1cc2ccccc2c(Br)c1O
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: [K+]
Solvent: COCCOC
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1O
Temperature: 80 °C
Yield: 98.1 %

Procedure:
A mixture of 2,4-dichlorophenylboronic acid (1.0 g), tetrakis(triphenylphosphine)palladium(0) (300 mg), 1-bromo-3-methyl-naphthalen-2-ol (5B, 625 mg) in K2CO3 (2 M, 5.3 mL) and DME (26 mL) was degassed with argon and sealed in a Schlenk tube. The reaction was heated to 80° C. for 75 minutes, then cooled to room temperature. The reaction was diluted with EtOAc and filtered through a pad of silica gel. The silica was washed with EtOAc and the combined organics were concentrated. The crude residue was purified by flash column chromatography (0-18% EtOAc in hexanes) to yield 784 mg of desired product.