Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2F)CCC1
Reaction time: 0.25 h

Procedure:
A 100 mL 3-neck round bottom flask was charged with 4-bromo-2-fluoro-1-iodobenzene (1000 mg, 3.32 mmol) and diethyl ether (30 mL). The solution was cooled to −78°G, and n-butyllithium (1.329 mL, 3.32 mmol) was added dropwise, keeping the temperature below −68° C. After stirring for 15 min, cyclobutanone (0.249 mL, 3.32 mmol) was added dropwise, keeping temperature below −68° C. The solution was stirred at −78° C. for 15 min. The reaction was then quenched by the addition of saturated ammonium chloride (25 mL). The layers were separated, and the organic was washed with water (1×10 mL) and brine (1×10 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2 gel), eluting with 3% ethyl-acetate/hexanes to give the desired product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.69 (m, 1H), 1.91-2.05 (m, 1H), 2.19-2.28 (m, 2H), 2.46-2.55 (m, 2H), 5.59 (s, 1H), 7.33-7.40 (m, 2H), 7.44-7.48 (m, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:6]=1.[CH2:20]([N:27]1[C:35]2[C:30](=[C:31]([Cl:37])[CH:32]=[C:33]([Cl:36])[CH:34]=2)[CH:29]=[C:28]1[C:38](O)=[O:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:38]([C:28]2[N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:35]3[C:30]([CH:29]=2)=[C:31]([Cl:37])[CH:32]=[C:33]([Cl:36])[CH:34]=3)=[O:39])[CH:6]=1
Reactant: COc1cc(NCCCN)nc2ccccc12
Reactant: O=C(O)c1cc2c(Cl)cc(Cl)cc2n1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COc1cc(NCCCNC(=O)c2cc3c(Cl)cc(Cl)cc3n2Cc2ccccc2)nc2ccccc12
Yield: 80 %

Procedure:
A solution of N1-(4-methoxyquinolin-2-yl)propane-1,3-diamine dihydrochloride (193 mg, 0.63 mmol) [from example 1d], 1-benzyl4,6-dichloro-1H-indole-2-carboxylic acid (203 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol), 1-hydroxybenzotriazole hydrate (94 mg, 0.70 mmol), and N-methylmorpholine (244 μl, 2.22 mmol) in anhydrous N,N-dimethylformamide (5 ml) was stirred for 2 days. The resulting slurry was taken into water (50 ml) and 10% sodium hydroxide solution (10 ml). Extracted into ethyl acetate. The extracts were dried (sodium sulfate) and evaporated to an oil. Column chromatography on silica (2:1 ethyl acetate/hexanes) gave 1-benzyl-4,6-dichloro-1H-indole-2-carboxylic acid [3-(4-methoxy-quinolin-2-ylamino)-propyl]-amide (269 mg, 80%) as a white solid. [M+H]+ 533.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4′-hydroxy-4-nitro-biphenyl (2.00 g, 7.51 mmol), prepared in the previous step, methyl bromoacetate (853 mL, 9.02 mmol) and potassium iodide (86 mg, 0.75 mmol) in 50 mL of acetone was stirred at room temperature until the mixture became cloudy. Potassium carbonate (2.26 g, 16.4 mmol) was added and the reaction refluxed overnight. The reaction was concentrated under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried (Na2SO4) and the solvent removed under reduced pressure to give (4′-nitro-biphenyl-4-yloxy)-acetic acid methyl ester.
Reaction SMILES: C([NH:4][C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[N:9]([CH2:19][CH2:20][CH2:21][CH3:22])[C:8]=2[NH:7][N:6]=1)(=O)C.[OH-].[Na+].Cl>C(O)C.O>[NH2:4][C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[N:9]([CH2:19][CH2:20][CH2:21][CH3:22])[C:8]=2[NH:7][N:6]=1
Reactant: CCCCn1c(=O)n(CCC)c(=O)c2c(NC(C)=O)n[nH]c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCn1c(=O)n(CCC)c(=O)c2c(N)n[nH]c21
Yield: 92.7 %

Procedure:
3-Acetylamino-7-butyl-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione(10 g) was heated under reflux for 5 hours in 80% ethanol(100 ml) containing sodium hydroxide (2 g). The reaction mixture was concentrated to give crystals. The crystals were suspended in water(100 ml), to which was added 6N-HCl to make it weakly acid to afford colorless crystals(8 g,93%),m.p. 209°-211° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41]C2C=CC(Br)=CC=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])C1C=CC=CC=1.[CH3:49][O:50][C:51]([C:53]1[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][CH:58]=1)=[O:52]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:15]2[CH:20]=[CH:19][C:18]([C:55]3[CH:56]=[CH:57][CH:58]=[C:53]([C:51]([O:50][CH3:49])=[O:52])[CH:54]=3)=[CH:17][CH:16]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:30])=[O:31])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2ccc(CN(C(=O)CN(C)S(=O)(=O)c3ccc(C)cc3)c3ccc(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3)cc2)c1

Procedure:
Aryl halide 9 was coupled to 3-(methoxycarbonyl)phenylboronic acid to give 28 on a 0.1 mmol scale via General Procedure H (65 mg, 62%): δH (400 MHz, CDCl3) 2.40 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.68 (s, 2H, CH2), 3.94 (s, 3H, CH3), 4.84 (s, 2H, CH2), 5.03 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.62 (s, 1H, CH), 6.68 (dd, J=8.0 and 1.6 Hz, 1H, CH), 7.19 (d, J=8.0 Hz, 2H, CH), 7.30-7.42 (m, 10H, CH), 7.52 (d, J=8.4 Hz, 2H, CH), 7.60-7.64 (m, 4H, CH), 7.78 (d, J=7.6 Hz, 2H, CH), 7.84 (d, 1H, J=8.0 Hz, CH), 8.02 (dt, J=8.0 and 1.2 Hz, 1H, CH), 8.25 (t, J=2.0 Hz, 1H, CH); δC (100 MHz, CDCl3) 21.5, 36.0, 52.2, 52.8, 56.0, 67.5, 70.7, 117.2, 117.5, 120.1, 125.2, 127.0, 127.2, 127.4, 127.5, 128.0, 128.1, 128.1, 128.2, 128.2, 128.5, 128.6, 128.9, 129.5, 130.7, 131.3, 133.2, 135.7, 135.7, 136.1, 139.5, 141.2, 142.4, 158.8, 161.7, 166.9, 167.0, 168.4; LRMS (ES+) calcd for [C46H42N2O8S+H] 783.27. found 783.26.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]#[N:41]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]#[N:41])[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCCCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCCCCCC#N)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 111.9 %

Procedure:
Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 6-bromo-hexanenitrile (0.33 g, 1.88 mmol) and following the procedure of Example 42(b) afforded 1.15 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (3H, m), 1.4 (9H, s), 1.6 (4H, m), 1.8 (6H, m), 3.2 (1H, m), 3.7 (1H, m), 4.05 (2H, m), 6.75 (1H, d), 6.90 (1H, s), 7.14 (3H, m), 7.34 (1H, s), 7.88 (2H, d), 8.28 (1H, d).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH2:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:13]([NH:5][CH2:4][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:12])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)C(CN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound is prepared from 3-methyl-2-phenyl-butylamine and benzaldehyde: A solution of 3-methyl-2-phenyl-butylamine (1.3 g, 8 mmol) and benzaldehyde (0.81 mL, 8 mmol) in CH2Cl2 (50 mL) is stirred at RT for 20 min. Sodium triacetoxyborohydride (2.52 g, 11.3 mmol) is then added, followed by acetic acid (0.46 mL, 8 mmol). The reaction mixture is stirred at RT for 16 h, then quenched by the addition of saturated NaHCO3 solution. The organic layer is separated and the aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated. The residue is purified by flash chromatography (hexane/ethyl acetate) to afford benzyl-(3-methyl-2-phenyl-butyl)-amine as a colourless oil. MS: 254.3 [M+H]+; tR (HPLC, C18 column; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.03 min.
Reaction SMILES: [OH:1][C@@H:2]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])[C@@H:3]([NH:5][C:6](=[O:29])[O:7][C@H:8]([CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:15]1)[C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:4].O[C@H](CNS(C1C=CC=CN=1)(=O)=O)[C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)C.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:4][C@H:3]([NH:5][C:6](=[O:29])[O:7][C@H:8]([CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=2)=[N:15]1)[C:9]([CH3:11])([CH3:10])[CH3:12])[C:2](=[O:1])[CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33]
Reactant: C[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: O=C([O-])O
Solvent: ClCCl
Product: C[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)C(=O)CNS(=O)(=O)c1ccccn1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a solution of 0.130 g (0.22 mmol) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 2.0 mL of dichloromethane was added 0.020 g (0.24 mmol) of sodium bicarbonate and 0.11 g (0.26 mmol) of Dess-Martin periodinane. The reaction mixture was stirred for 15 min and then purified via silica gel chromatography eluting with ethyl acetate:hexane (7:3) to afford 0.078 g (59%) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 8.58 (m, 1H), 7.98–7.89 (m, 4H), 7.63 (m, 2H), 7.46 (m, 2H), 6.65 (s, 1H), 5.56 (m, 1H), 1.05 (s, 9H), 5.24 (d, J=7 Hz, 1H), 4.98 (m, 1H), 4.44 (m, 1H), 4.34–4.12 (m, 4H), 1.12 (d, J=7 Hz, 3H); LC-MS m/z 582 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][O:24][CH2:29][CH:28]=[CH2:27])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@](CO)(c2ccc(Cl)c(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)OC(C)(C)C)CCO1
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (7S)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1.01 g) in DMF (7 mL) was added sodium hydride (129 mg) at 0° C. After stirring for 10 min, allyl bromide (0.272 mL) was added, and the mixture was stirred at room temperature for 10 min. Under ice-cooling, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (917 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:1]([N:8]1[C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1cncn1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C(=CCc2ccccc2)c2cncn2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Titanium tetrachloride (0,03 mol) is added dropwise to a stirred suspension of zinc powder (0,06 mol) in tetrahydrofuran (30 ml) at -10° C. under dry nitrogen. The mixture is heated to reflux and refluxing is continued for 1 hour. The solution is cooled to 0° C. and 1-benzyl-5-[1-(4-fluorophenyl)-1-oxomethyl]-1H-imidazole (0,005 mol) in tetrahydrofuran (10 ml) and phenylacetaldehyde (0,006 mol) in tetrahydrofuran (10 ml) are added into the mixture, respectively. The mixture is refluxed with stirring for 1 hour. The dark mixture is poured into water (60 ml), tetrahydrofuran is evaporated and the mixture is extracted with methylene chloride (2×100 ml). The methylene chloride solution is washed with 2N sodium hydroxide and water, dried with sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]([O:13]CC2C=CC=CC=2)=O)[CH:5]=[CH:6][C:7]=1[I:8].[OH-].[Na+].F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=N1.C1(N)C(N)=CC=CC=1.C(N(CC)C(C)C)(C)C>C(#N)C.O.Cl.CN(C=O)C.C(OCC)(=O)C>[NH2:38][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:40][C:11](=[O:13])[C@@H:10]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([I:8])=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)C(=O)OCc1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Br)c1)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
Benzyl (2S)-3-(3-bromo-4-iodophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (1.50 g, 2.68 mmol) was dissolved in acetonitrile (7.5 mL) and treated with 1.0 M of sodium hydroxide in water (5.4 mL). The solution was stirred at 25° C. for 30 min. The reaction was diluted with 1 N HCl solution and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude was dissolved in DMF (4.0 mL) and treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.03 g, 2.34 mmol) at 0° C. for 15 min. A solution of 1,2-benzenediamine (345 mg, 3.19 mmol) and N,N-diisopropylethylamine (1.85 mL, 10.6 mmol) in DMF (4.0 mL) was added to the reaction. The resulting mixture was warmed to room temperature for 2 h. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution (50 mL) and 1 N HCl solution (50 mL). The organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS to yield the desired product (0.71 g, 60%). 1H NMR (400 MHz, CDCl3): δ 7.85 (d, 1H), 7.62 (s, 1H), 7.25–6.98 (m, 5H), 4.40 (t, 1H), 3.11 (dd, 1H), 2.91 (dd, 1H), 1.41 (s, 9H); LCMS found for C20H24BrIN3O3 (M+H)+: m/z=560, 562.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=[N:17][OH:18])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].C[Si]([N:23]=[C:24]=[O:25])(C)C>C1COCC1>[C:24]([O:18][N:17]=[C:13]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)[CH:14]([CH3:16])[CH3:15])(=[O:25])[NH2:23]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)C(=NO)c1c(C(C)C)nn2ccccc12
Solvent: C1CCOC1
Product: CC(C)C(=NOC(N)=O)c1c(C(C)C)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To a solution of 376 mg (1.53 mol) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 2 ml of anhydrous THF was added 540 μl of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The reaction was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue obtained was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 200 mg (45.3%.) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1014.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1F

Procedure:
The title compound was prepared from the product of Example 65A and 3-fluoro-4-methoxyphenylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 354.0 (M+H)+, retention time 1.80 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: Cc1nc[nH]n1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 26.2 %

Procedure:
A mixture of 3-methyl-1H-1,2,4-triazole (5.0 g, 60.2 mmol), 1-chloro-2-methoxy-4-nitrobenzene (11.3 g, 60.2 mmol), and KOH flakes (3.4 g, 48.1 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 6 h. The reaction mixture was allowed to cool to rt and was poured into 800 mL of water with vigorous stirring. The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-2% MeOH/chloroform, linear gradient) to afford 1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 26% yield). LC-MS (M+H)+=235.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH:12]=[O:13])[C:6]([CH3:15])([CH3:14])[CH2:5]2.[H-].[Na+].Cl[CH2:20][C:21]([CH3:23])=[CH2:22].[Cl-].[NH4+]>CN(C=O)C>[CH3:15][C:6]1([CH3:14])[CH2:5][C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([O:1][CH2:22][C:21]([CH3:23])=[CH2:20])[C:3]=2[CH3:16])[N:7]1[CH:12]=[O:13]
Reactant: Cc1cc(O)c(C)c2c1N(C=O)C(C)(C)C2
Reactant: C=C(C)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C)c2c(c1C)CC(C)(C)N2C=O
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-2,2,4,7-tetramethyl-1H-indole-1-carbaldehyde (2.29 g, 10.4 mmol) in DMF (15 ml) was added 60% dispersion of sodium hydride in oil (0.42 g, 12 mmol) with cooling on ice and stirred under nitrogen atmosphere at the same temperature for 5 minutes. To the resulting mixture was added 3-chloro-2-methyl-1-propene (1.3 ml, 13 mmol) and stirred at room temperature for 30 minutes and at 60° C. for 15 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to obtain 1.95 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](\[CH3:13])/[C:10]([OH:12])=[O:11].[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23]O)[CH3:21])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1CCCCC1.CCCCCC>[CH3:21][CH:20]([CH2:19][CH2:18][CH:17]=[C:15]([CH3:16])[CH3:14])[CH2:22][CH2:23][O:11][C:10](=[O:12])/[C:9](/[CH3:13])=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: C/C(=C\c1ccccc1O)C(=O)O
Reactant: CC(C)=CCCC(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)=CCCC(C)CCOC(=O)/C(C)=C/c1ccccc1O

Procedure:
A solution of 6 0 g of (E)-3-(2-hydroxy-phenyl)-2-methyl-acrylic acid, 5.3 g of citronellol and 1 g of p-toluene-sulfonic acid in 150 ml of cyclohexane was refluxed for 6.5 hours using a water separator. Then the reaction mixture was cooled down, diluted with hexane and washed to neutrality with saturated sodium bicarbonate and water. The organic phase was dried, filtered and evaporated to dryness. The resulting yellow oil was purified by chromatography to yield 6.45 g of a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[C:12]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[C:15]([O:14][C:12]([N:19]1[CH2:22][CH:21]([NH:23][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[C:8]([O:10][CH3:11])=[O:9])[CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ncsc1CBr
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ncsc1CNC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixture of compound 3b (250 mg, 1.06 mmol), 1-Boc-3-aminoazetidine 1a (310 mg, 1.80 mmol), and K2CO3 (248 mg, 1.80 mmol) in THF (12 mL) was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The resulting solution was washed with aq. NaHCO3, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 3c (210 mg).