Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[N:9]=[C:10]([O:22][CH3:23])[C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:13]=1.[H][H]>CO.[Pd]>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:12]2[CH:13]=[CH:8][N:9]=[C:10]([O:22][CH3:23])[C:11]2=[O:21])=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COc1nc(Cl)cn(-c2ccc(F)cc2)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1nccn(-c2ccc(F)cc2)c1=O
Reaction time: 6 h
Yield: 89.7 %

Procedure:
K2CO3 (1.09 g, 7.85 mmol) and 10% Pd/C (0.42 g, 0.39 mmol) were added to 5-chloro-1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one (2.0 g, 7.85 mmol) in MeOH (100 mL) at room temperature. Hydrogen gas was treated with balloon to the reaction mixture. After 6 hours stirring, the reaction mixture was filtered with MeOH and concentrated under reduced pressure. The crude was treated with CH2Cl2, washed with water, dried over MgSO4, and concentrated to give the desired product (1.55 g, 90%). LRMS (ESI pos) m/e 221.0 (M+1). 1H-NMR (400 MHz, CDCl3) δ 7.49 (m, 2H), 7.27 (t, 2H), 7.10 (d, 1H), 6.98 (d, 1H), 3.98 (s, 3H); 19F-NMR (376 MHz, CDCl3) δ −114.7.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([F:20])([F:19])[CH2:17]I.O>CS(C)=O>[F:15][C:16]([F:20])([F:19])[CH2:17][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
To a solution of catechol (5 g, 0.045 moles) in dimethylsulfoxide (25 ml) were added, potassium carbonate (12.55 g, 0.09 mole) and 2,2,2-trifluoroethyl iodide (4.77 g, 0.023 mole) under stirring. The reaction mixture was stirred vigorously at 120° C. for 6 hours. Water (150 ml) was added to the reaction mixture and the mixture was extracted in Toluene (250 ml). Organic layer was washed with 1 N Sodium hydroxide solution (150 ml), followed by brine wash. The extract was dried over sodium sulphate. The solvent was evaporated under reduced pressure to give 4.0 g of (XI) as oil. Purity (by GC)=96%
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[Cl-].[NH4+]>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butylmagnesium chloride (0.93 mol/l solution in tetrahydrofuran, 75.5 mL, 70.26 mmol) was added to a solution of 3-bromobenzaldehyde (10 g, 54.05 mmol) in tetrahydrofuran (100 mL) in a nitrogen atmosphere at −78° C. The mixture was stirred at the same temperature for one hour and then heated to room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to give crude 1-(3-bromo-phenyl)-2,2-dimethyl-propan-1-ol.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:19][C:17]1[CH:18]=[CH:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([NH:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)[CH:16]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: NC1CCOc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccccc21
Yield: 58.6 %

Procedure:
A solution of chroman-4-amine (0.38 g, 2.55 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (0.49 g, 2.55 mmol) and diisopropylethylamine (2.2 mL, 12.74 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried, and concentrated under reduced pressure to yield 0.48 g of a yellow oil. The residue was purified by PTLC (25% ethyl acetate in hexanes) to give 0.45 g (55%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, 1H), 7.35 (d, 1H), 7.28 (m, 1H), 6.91 (m, 1H), 6.85 (d, 1H), 6.57 (dd, 1H), 6.42 (dd, 1H), 4.49 (m, 1H), 4.34 (bs s, 1H), 4.29 (m, 2H), 2.86 (s, 3H), 2.23 (m, 2H). MS (ESI) m/z: Calculated: 321.08; Observed: 322.2 (M++1).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>CC(O)(C)C>[CH3:12][O:11][C:9]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C@@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:10]
Reactant: O=C1C=CCC1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)[C@@H]1CCC(=O)C1
Temperature: 30 °C
Reaction time: 72 h
Yield: 99.2 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=100) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 168 μL (2.0 mmol) of 2-cyclopentenone, 228 μl (2.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 72 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 425 mg (99% yield) of the title compound. The optical rotation [α]D21 was +96.3 (c 0.54, CHCl3). The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm) and it was found to be 98% ee.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[N+:8]=[N-:9].[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CS(C)=O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[C:22]([CH:18]2[CH2:19][CH2:20][CH2:21][O:17]2)=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:9]=[N:8]1
Reactant: CCOC(=O)CC(=O)C1CCCO1
Reactant: [N-]=[N+]=Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C1CCCO1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (2.419 g; 17.50 mmol; 2 eq.) was dissolved in DMSO (18 ml) and put under nitrogen atmosphere. 1-Azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.2 g; 8.75 mmol; 1 eq.) was dissolved in 10 mL of DMSO and ethyl 3-(tetrahydrofuran-2-yl)-3-oxopropanoate (Pharmacore, 1.793 mg; 9.63 mmol; 1.10 eq.) was added. This solution was added dropwise to the potassium carbonate solution at room temperature. The mixture was stirred at 70° C. for 3 hours. Water (30 mL) was added to the mixture and it was extracted with EtOAc (2×40 mL). Organics were washed with brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a brown oil. It was used in the next step without further purification. HPLC (Method A) Rt 4.14 min (Purity: 86.6%).
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=O.[CH:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH:11]1[NH2:20])[CH2:17]2.[OH-:21].[Na+]>O>[NH2:20][CH:11]1[CH:12]2[CH2:18][C:16]3([OH:21])[CH2:15][CH:14]([CH2:19][CH:10]1[CH2:17]3)[CH2:13]2
Reactant: [OH-]
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Concentrated sulfuric acid (35 mL) was mixed with concentrated nitric acid (4.5 mL) and 2-adamantylamine (5.10 g, 4.57 mmol) under cooling with ice, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water and adjusted to pH 10 with 7.5 M aqueous sodium hydroxide. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a yellow solid (2.79 g, yield 61%).
Reaction SMILES: C1C2(CCCC=C2C(=O)C)CC=C1.O[CH:15]([CH3:29])[CH2:16][C:17]([C:19]1[C:20]2([CH2:25][CH2:26][CH2:27][CH:28]=1)[CH2:24][CH:23]=[CH:22][CH2:21]2)=[O:18].CC(OC(C)=O)=O.C(O[Na])(C)=O>CCCCCC.CC(OC)(C)C>[CH2:24]1[C:20]2([CH2:25][CH2:26][CH2:27][CH:28]=[C:19]2[C:17](=[O:18])/[CH:16]=[CH:15]/[CH3:29])[CH2:21][CH:22]=[CH:23]1
Reactant: CC(O)CC(=O)C1=CCCCC12CC=CC2
Agent: CC(=O)C1=CCCCC12CC=CC2
Agent: CC(=O)O[Na]
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: CC(=O)OC(C)=O
Product: C/C=C/C(=O)C1=CCCCC12CC=CC2

Procedure:
Prepared as described in Example 10, from 1-(spiro[4.5]deca-2,6-dien-6-yl)ethanone via 3-hydroxy-1-(spiro[4.5]deca-2,6-dien-6-yl)butan-1-one (LDA, acetaldehyde, THF, 72% after FC (SiO2, hexane/MTBE 1:1); 17% starting material recovered) and subsequent Ac2O/AcONa treatment (35% after FC (SiO2, hexane/MTBE 30:1)). Boiling point: 110° C. (0.08 mbar).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[NH:1][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3N)cc2)CC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 71.1 %

Procedure:
A mixture of tert-butyl 4-[4-(2-amino-5-chlorophenoxy)phenyl]piperazine-1-carboxylate (3.8 g, 9.5 mmols), ethyl 4-bromobutyrate (2.7 ml, 19 mmols), potassium carbonate (1.3 g, 9.5 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[4-(4-tert-butoxycarbonyl-1-piperazinyl)phenoxy]-4-chlorophenyl]aminobutyrate (3.5 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:15]([N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28]2)=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]2=[C:8]([C:26]3[CH:27]=[CH:28][C:29]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]=4)[CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCO)cc(Br)c12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1ncnn2c(CCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-ethanol (425 mg, 1.65 mmol) and 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (828.8 mg, 2.48 mmol, 1.5 eq) were dissolved in 1:1 EtOH-toluene (33 mL each) and degassed with nitrogen. After 30 minutes, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexed with dichloromethane (121 mg, 0.17 mmol, 0.1 eq) followed by 2M aqueous sodium carbonate solution (1.65 mL, 3.31 mmol, 2.0 eq) were added. The reaction mixture was stirred at 80° C. for 17 h and cooled to rt. The reaction mixture was partitioned between EtOAc and water and filtered through a pad of Celite® to remove excess palladium salts. The organic layer was washed with water and brine, dried over Mg2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 1 to 100% [20% MeOH/DCM+1% Et3N]/DCM) and the product containing fractions were concentrated. Trituration with DCM-hexane gave 232.3 mg (36%) of the title compound as beige solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.88 (s, 1H), 7.79 (d, 1H), 7.56 (s, 1H), 7.34-7.28 (m, 5H), 7.13 (dd, 1H), 6.62 (s, 1H), 5.64 (s, 2H), 4.76 (t, 1H), 3.72 (q, 2H), 3.04 (t, 2H); ES-MS m/z 385.2 [M+H]+, RT (min) 2.25.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([C:32]4[C:23](=[CH:24][C:25]5[O:30][CH2:29][CH2:28][O:27][C:26]=5[CH:31]=4)[O:22][CH2:21]3)[C:13]2=[O:33])[CH:6]=1)[NH2:4].ON=[C:36]([C:38]1C=CC=C(CN2C3C(=CC=CC=3)C3(COC4C=C5C(=CC3=4)CCO5)C2=O)C=1)N>>[CH3:36][C:38]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=2)[CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([C:32]4[C:23](=[CH:24][C:25]5[O:30][CH2:29][CH2:28][O:27][C:26]=5[CH:31]=4)[O:22][CH2:21]3)[C:13]2=[O:33])[N:4]=1
Reactant: NC(=NO)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Reactant: NC(=NO)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1nc(-c2cccc(CN3C(=O)C4(COc5cc6c(cc54)OCCO6)c4ccccc43)c2)no1

Procedure:
Following the procedure as described in EXAMPLE 11.27 and making non-critical variations using N′-hydroxy-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide to replace N′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide, 1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: mp 90-95° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.89-7.87 (m, 2H), 7.58-7.53 (m, 2H), 7.25-7.15 (m, 2H), 7.03-6.95 (m, 2H), 6.50 (s, 1H), 6.20 (s, 1H), 5.15-4.64 (m, 4H), 4.16-4.07 (m, 4H), 2.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.1, 177.3, 167.8, 155.2, 144.7, 142.4, 138.4, 137.9, 132.2, 130.8, 130.2, 129.3, 127.2, 126.3, 125.5, 124.2, 123.7, 121.5, 111.6, 109.9, 99.3, 80.0, 64.7, 64.0, 57.8, 43.1, 12.4; MS (ES+) m/z 467.8 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[C:15](O)=[O:16])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].S(Cl)([Cl:23])=O>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[C:15]([Cl:23])=[O:16])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)Cl)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3.81 g (14 mmol) of the above pyridone acid and 100 ml of thionyl chloride is stirred at 45° for 1 hr and at room temperature overnight. The reaction mixture is stirred for 3 hrs at 52°, cooled, and filtered. The solid is washed with hexane and dried under high vacuum over phosphorus pentoxide to give 3.57 g of 6-[3-(acetylamino)phenyl]-1,2-dihydro-2-oxonicotinoyl chloride.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29]C)[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl>[CH:1]([N:14]1[CH2:15][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)c1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(O)c1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
10 cm3 of a 1 M solution of boron tetrabromide in dichloromethane are added, with stirring, to a solution of 1.3 g of 1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine in 100 cm3 of dichloromethane. The stirring is maintained for 16 hours at room temperature. The reaction medium is taken up in 100 cm3 of ice-cold water. The organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 150 cm3 of isopropyl ether and then dissolved in 50 cm3 of dichloromethane. The organic phase is washed with 3 times 30 cm3 of a saturated aqueous solution of sodium bicarbonate, decanted off, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 80 cm3 of ethyl ether. 0.36 g of 1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine is obtained from a solid melting at 248° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.85 (3H, m, 3 CH arom.), 7.25 (3H, m, 3 CH arom.), 7.35 (4H, t, J=7 Hz, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.), 9.50 (1H, s, OH)].
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:6][NH:5][C:4](=[O:24])[CH2:3]1.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].Cl>[OH-].[Na+].O>[CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:6][NH:5][C:4](=[O:24])[CH:3]=1
Reactant: CC1CC(=O)NN=C1c1ccccc1OCC(O)CNC(C)(C)C
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1cc(=O)[nH]nc1-c1ccccc1OCC(O)CNC(C)(C)C
Yield: 31 %

Procedure:
5-Methyl-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3[2H]-pyridazinone (preparable from British Patent Specification No. 1488330) (1.3 g) and sodium 3-nitrobenzene sulphonate (0.88 g) were mixed in aqueous sodium hydroxide (0.38 g in 50 ml) and stirred under reflux for 3 hours. The reaction mixture was cooled, neutralised with hydrochloric acid and evaporated under reduced pressure to afford a residue. This was dissolved in water, on standing a solid precipitated which was filtered off (recovered sodium 3-nitrobenzene sulphonate). The filtrate was shaken with chloroform whereupon a white solid precipitated which was collected and dried to afford the title compound (0.4 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.C(O)(=O)C.Cl.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1([C:47](=N)OCC)[CH2:46][CH2:45]1>C(O)C>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1([C:47]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH2:45][CH2:46]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2ccccc2OC)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1ccccc1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 75 °C

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (32 mg, 0.088 mmol) in ethanol (0.5 mL) was added triethylamine (50 μL, 1.42 mmol) and acetic acid (82 μL, 1.42 mmol). Then a solution of ethyl 1-(2-methoxyphenyl)cyclopropanecarbimidate hydrochloride (50 mg, 0.09 mmol) in ethanol (0.3 mL) was added and the reaction mixture was heated to 75° C. for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 446.1; HPLC retention time: 2.299 min (Method A).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH:20]1([NH:23][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=[C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: COCCCc1cc(CCCOC)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-bis(3-methoxypropyl)benzoic acid (1 eq.) from the previous step in DCM (0.1 M) was added cyclopropanamine (1.3 eq.), o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (aka. HATU, 1.5 eq.), and triethylamine (3 eq.). After stirring at rt for 18 h, the reaction was diluted with EtOAc. The organic extract was washed with 10% aqueous HCl solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 50%→>70% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13](C(OC(C)(C)C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.O>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:34])[CH3:35])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[[(5-chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 7) (3.12 g, 5.43 mmol) in DMF (20 mL) was added a solution of sodium carbonate (0.864 g, 8.15 mmol) in water (20 mL) at room temperature. A white suspension was obtained and a warming of the medium was noticed. The resulting suspension was stirred overnight at 80° C., the reaction mixture was then cooled to room temperature, and more sodium carbonate (300 mg) was added. The resulting mixture was then stirred at 85° C. After 3 h of stirring, 50 mL of water and 50 mL of DCM were added to the reaction mixture. The organic layer was partitioned and the aqueous layer was further extracted with 30 mL of DCM. The organic solutions were combined, dried with an hydrophobic frit and concentrated under reduced pressure. The crude oil was purified by chromatography on two 100 g Si cartridges on Flashmaster, eluting with a 0 to 25% gradient of EtOAc in cyclohexane, over 25 min. The pure fractions were combined to give the title product as an orange gum (1.62 g, 63%) LCMS (System A) RT=1.41 min, ES+ve m/z 474/476 (M+H)+. Impure fractions were combined and repurified by chromatography on a 70 g silica cartridge on Flashmaster, eluting with a 0 to 25% gradient of EtOAc in cyclohexane over 40 min. Fractions containing pure product were combined to give more of the desired product (277 mg, 11%)