Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([O:16]C)=[O:15].O.NN.[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](C(=O)C)[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2.Cl>CO>[F:21][C:22]1[C:31]([CH:32]([C:34]2[N:38]3[N:39]=[C:40](/[C:2](=[N:3]/[O:12][CH2:13][C:14]([OH:16])=[O:15])/[CH3:10])[CH:41]=[CH:42][C:37]3=[N:36][N:35]=2)[CH3:33])=[C:30]([F:46])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Reactant: COC(=O)CON1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: C/C(=N\OCC(=O)O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Methyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (237 mg, 1.01 mmol) and hydrazine monohydrate (50 mg, 1.0 mmol) were dissolved in methanol (3 mL) and heated at 70° C. for 2 h. After filtration, the solid was washed with EtOAc. The combined solution was concentrated and the residue was diluted with methanol. A solution of NaOH (6 N, 3 mL) was added and the mixture was stirred at 70° C. for 2 h. The solution was concentrated, acidified with 3 N HCl to pH 1 and filtered. The solid was washed with water, and the combined solution was concentrated. The residue was diluted with DCM, then ketone 53.5 (40 mg, 0.113 mmol) and HCl (4 N HCl in dioxane, 0.7 mL) were added. It was stirred at rt for 24 h. After concentration, the residue was purified by prep-HPLC to give 21 mg (34%) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.90 (s, 1H), 8.97 (d, 1H), 8.45 (d, 1H), 8.26 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.27 (q, 1H), 4.76 (s, 2H), 2.03 (d, 3H), 1.94 (s, 3H). LCMS (method B): [MH]+=427, tR=2.259 min. Chiral separation (method L) provided enantiomeric pure compounds example 68-R (tR=7.71 min) and example 68-S (tR=9.99 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>ClCCl>[CH3:26][C:23]([CH3:27])([NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:24][OH:25]
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 67.1 g (0.322 mole) of 4-chloro-3-nitroquinoline in 800 mL cf dichloromethane was added 54 mL (0.38 mole) of triethylamine and 96 mL (0.96 mole) of 2-amino-2-methyl-1-propanol. The mixture was heated at reflux for one hour, then stirred at about 20° C. for about 16 hours. The mixture was concentrated by evaporation in vacuo and the residue was slurried in 1.5 1 of water. The product was separated by filtration and dried to provide solid 2,2-dimethyl-2-[(3-nitro-4quinolinyl)amino]ethanol. The structural assignment was confirmed by comparison of the nuclear magnetic resonance spectrum to that of a sample which was previously used for elemental analysis. Analysis of earlier sample: Calculated for C13H15N3O2 : %C, 59.8; %H, 5.8; %N, 16.1; Found %C, 59.9; %H, 5.8; %N, 16.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
4-Chlorophenylacetic acid (1.7 g, 10 mmol) and oxalyl chloride (2 ml, 23 mmol) were stirred in 100 ml methylene chloride with two drops of dimethylformamide for two hours. The solvent and excess oxalyl chloride were removed under vacuum to give p-chlorophenylacetyl chloride. The 4-chlorophenylacetyl chloride and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.5 g, 8.2 mmol) were dissolved in methylene chloride. Triethylamine (3 ml) was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), 5% potassium carbonate (5% K2CO3) and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 15 ml acetonitrile. Triethylamine (3 ml) and acetone cyanohydrin (0.3 g) were added and the mixture stirred at room temperature for 4 hours. After dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated under vacuum yielding 1.0 g of an oil that solidified on standing (m.p. 57°-61° C.). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][CH2:25]C(OCC)=O)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:31][Mg]Br.[CH2:34]1[CH2:38][O:37]CC1>>[CH3:31][C:38]([OH:37])([CH2:25][CH2:24][C:22]1[S:23][C:19]([C:4]2[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:20][N:21]=1)[CH3:34]
Reactant: CCOC(=O)CCc1ncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CCC(C)(C)O)s2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Ethyl 3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-propanoate (Example 79-1, 100 mg, 0.229 mmol) was taken up in THF (5 mL) and cooled to −78° C. Methylmagnesium bromide (3.0 M in Et2O, 305 μL, 0.916 mmol) was added, and the reaction was stirred at −78° C. for 90 min. It was then warmed to room temperature. After 1 h at room temperature, the reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Column chromatography on silica (20-100% ethyl acetate in hexanes) afforded 2-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]butan-2-ol (73 mg, 75%) as a white foam. MS ESI: [M+H]+ m/z 423.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=4.8, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.42 (s, 1H), 7.25 (d, J=4.8, 1H), 7.11 (s, 1H), 436 (s, 1H), 3.05-2.92 (m, 2H), 2.28 (s, 3H), 1.87-1.73 (m, 2H), 1.11 (s, 6H). rhSYK activity=+++
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:22])[N:6]=1)[CH2:3][CH3:4].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.CCN(C(C)C)C(C)C>C(O)(C)(C)C.CCO>[F:22][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13](=[O:21])[N:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5]([C@@H:2]([NH:1][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH2:3][CH3:4])=[N:6]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A suspension of compound 111 (65.6 mmol, 1 eq), 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq), and DIEA (24.3 mL, 140 mmol, 2 eq) in tert-butanol (40 mL) was stirred for 24 h at 80° C. The reaction mixture was concentrated in vacuo and treated with water to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried. Half of the obtained solid crude product was dissolved in MeOH (600 mL), concentrated onto silica gel (300 mL dry), and purified by flash chromatography (7.5×36 cm, eluted with 10 L of 4% MeOH/CH2Cl2) to yield a solid product. The solid product was then dissolved in EtOH (250 mL) and concentrated in vacuo to compound 107 as a light yellow solid (7.2 g, 50%). 1H NMR (300 MHz, 80° C., DMSO-d6) δ 12.66 (broad s, 1H), 8.11 (s, 1H), 8.02 (broad s, 1H), 7.81-7.73 (m, 1H), 7.60-7.42 (m, 6H), 7.25-7.15 (m, 2H), 4.97 (broad s, 1H), 2.02-1.73 (m, 2H), 0.79 (t, J=7.3 Hz, 3H). ESI-MS m/z 416.2 (MH+). C, H, N elemental analysis (C22H18N7OF.EtOH.0.4H2O). Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6×250 mm Chiralpak ODH column, 20° C., 85:15 hexanes:EtOH, 1 mL/min, sample loaded at a concentration of 1 mg/mL in EtOH). The reaction described above and compound 107 are shown below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2ncccc2[N+](=O)[O-])C1
Temperature: 110 °C

Procedure:
Tert-butyl(trans-3-aminocyclobutyl)carbamate (1.38 g, 7.41 mmol), 2-chloro-3-nitropyridine (1.25 g, 7.88 mmol) and potassium carbonate (0.655 ml, 10.85 mmol) were combined in dry dimethylsulfoxide (20 mL) and heated at 110° C. After 2 hours the reaction was cooled and partitioned between ethyl acetate (300 mL) and water (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired tert-butyl(trans-3-((3-nitropyridin-2-yl)amino)cyclobutyl)carbamate (1.45 g, 4.70 mmol, 63.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)ccc1F

Procedure:
Example 49 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.34–8.20 (m, 1H), 7.46–7.14 (m, 5H), 7.10–6.95 (m, 1H), 6.92–6.77 (br, 1H), 6.74–6.59 (br, 1H), 3.39–3.25 (m, 2H), 3.00–2.82 (m, 2H), 2.67–2.51 (m, 1H), 2.51–2.40 (m, 1H), 2.40–2.27 (m, 2H), 2.03–1.86 (m, 2H), 1.85–1.71 (m, 2H), 1.71–1.57 (m, 4H), 1.56 (s, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:28]([O-])=O)[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:28][C:4]1[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1N
Yield: 92.8 %

Procedure:
To a solution of 2-(5-chloro-3-nitro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (1.25 g, 2.86 mmol) in ethanol (50 mL) was added platinum dioxide (0.92 g). The mixture was hydrogenated on a Parr shaker at 35 psi of hydrogen for 5 minutes at ambient temperature. The reaction was then purged with nitrogen and filtered through celite. The filtrate was concentrated in vacuo to give the title compound (1.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20][CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+].Cl>[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20](=[O:23])[CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CSCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CS(=O)CC3

Procedure:
To a solution of 0.29 g of 2-p-chlorophenyl-2,3,5,6,7,9-hexahydrothiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one in a mixture of 9.2 mL of 0.1N sodium hydroxide aqueous solution and 15 mL of water, 0.215 g of sodium metaperiodate is added under stirring and ice-cooling. The reaction mixture is stirred at room temperature overnight, the pH of the solution is adjusted to around 4 by adding dilute hydrochloric acid to precipitate a yellow solid. Solid is collected, washed with water, air-dried, triturated with hot ethyl acetate and dried in a vacuum oven at 80° overnight obtaining 2-p-chlorophenyl-2,3,5,6,7,9-hexahydro-8-oxo-thiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one, m.p. 298°-300° (dec).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:16]([CH3:17])=[CH:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:13]=1)=[O:11]>COCCOC.C(Cl)(Cl)Cl.CO>[ClH:9].[NH:7]([C:10]([C:12]1[C:16]([CH3:17])=[CH:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: Cc1cn(-c2nccc3ccccc23)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2nccc3ccccc23)cc1C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
1.37 g (25.37 mmol) of sodium methoxide are added at a temperature in the region of 20° C. under an argon atmosphere to 25 mL of methanol. After complete dissolution, 2.5 g (26.2 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 20° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is suspended in 25 mL of 1,2-dimethoxyethane and then again concentrated to dryness. The residue is suspended in a mixture of 50 mL of tetrahydrofuran, 25 mL of acetonitrile and 50 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere and then 1.18 g (4.36 mmol) of 3-chlorocarbonyl-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole, dissolved in 20 mL of chloroform, are added thereto. After stirring at a temperature in the region of 20° C. for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 100 mL of water. After filtering, a gum is obtained, which gum is dissolved in 50 mL of methanol. The solution obtained is partially concentrated to a volume of 5 to 10 mL and is then purified by silica gel chromatography [eluent: chloroform/methanol (75/25 by volume)]. After concentrating the fractions under reduced pressure and triturating in ethyl ether, 0.62 g of 3-guanidinocarbonyl-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole hydrochloride is obtained in the form of a white solid melting at 247° C. Mass spectrum (EI): EI: m/e 293 (M+.), m/e 234.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])[C:4](=O)[CH3:5])#[N:2].O.[NH2:16][NH2:17].C(O)(=O)C>C1(C)C=CC=CC=1>[NH2:2][C:1]1[NH:17][N:16]=[C:4]([CH3:5])[C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14]
Reactant: CC(=O)C(C#N)c1ccc(C)cc1C
Reactant: NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2c(C)n[nH]c2N)c(C)c1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A mixture of 1-cyano-1-(2,4-dimethylphenyl)propan-2-one (43.8 g, 0.23 mol), hydrazine-hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0.78 mol) and toluene (500 mL) were stirred at reflux temperature for 18 hours in an apparatus fitted with a Dean-Stark trap. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was dissolved in 6N HCl and the resulting solution was extracted with ether three times. A concentrated ammonium hydroxide solution was added to the aqueous layer until pH=11. The resulting semi-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDCl3, 300 MHz): 7.10 (s, 1H), 7.05 (d, 2H, J=1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS: 202 (M+H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:34])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[O:43][N:42]=[C:41]([CH2:44][NH2:45])[CH:40]=1.CS(C)=O.C(N(CC)CC)C>C(#N)C>[CH3:38][C:39]1[O:43][N:42]=[C:41]([CH2:44][NH:45][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=5[CH3:33])=[C:23]([CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:40]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1c(C)cccc1C
Reactant: Cc1cc(CN)no1
Solvent: CC#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4c(C)cccc4C)c(C)c2)C3)no1

Procedure:
The title compound was prepared according to the procedure of Example 2 starting from 2,2,2-trichloro-1-{10-[(2,2′,6′-trimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 3 (1.8 g, 3.26 mmole), (5-methyl-3-isoxazolyl)methylamine (0.305 g, 2.7 mmole), dimethylsulfoxide (1.06 g, 13.6 mmole), and triethylamine (0.605 g, 6 mmole) in 20 mL of acetonitrile. The residue was flash chromatographed on silica Merck-60 using a gradient from 0 to 35% of ethyl acetate in dichloromethane, to provide an orange-yellow foam. Recrystallization from ethyl acetate/dichloromethane/hexane gave a white powder (0.334 g), m.p. 233-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[I:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[I:30])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4nccc34)CC2=O)cc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(I)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(R)-4-((R)-1-((6-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (216 mg, 0.522 mmol) was dissolved in acetonitrile (10.0 mL) and N-iodosuccinimide (124 mg, 0.548 mmol) was added. The solution was stirred at room temperature for 5 minutes. The reaction was diluted with DCM. The organic layer was washed with 1M NaOH followed by an aqueous solution of sodium thiosulfate. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford (R)-4-((R)-1-((6-chloro-3-iodopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.CO.C(Cl)(Cl)Cl.CO>CCOC(C)=O>[NH2:27][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]([O:25][CH3:26])=[CH:23][C:12]=1[C:13]([N:15]1[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]1[CH2:21][OH:22])=[O:14]
Reactant: C=C1C[C@@H](CO)N(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])C1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C1C[C@@H](CO)N(C(=O)c2cc(OC)c(OCc3ccccc3)cc2N)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
The nitro-alcohol 66 (0.637 g, 1.60 mmol), SnCl2 2H2O (1.81 g, 8.0 mmol) and methanol (36 mL) were heated at reflux and monitored by TLC (90% CHCl3/MeOH). After 1 hour the MeOH was evaporated in vacuo and the resulting residue cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give an orange glass. Flash chromatography (EtOAc) afforded the pure amine 67 as a pale yellow glass (0.37 g, 63%): [α]23D=−42.7° (c=3.7, CHCl3); 1H NMR (270 MHz, CDCl3) δ7.44-7.29 (m, 5Harom), 6.77 (s, 1Harom) 6.27 (s, 1Harom), 5.12 (s, 2H, PhCH2O), 5.06-5.00 (m, 1H, NCH2C═CH2), 4.99-4.92 (m, 1H, NCH2C═CH2), 4.63-4.53 (m, 1H, NCHCH2OH), 4.25-3.60 (m, 10H, NCHCH2OH, NCH2C═CH2, OCH3, OH and NH2), 2.77 (dd, 1H, J=8.52, 15.85 Hz, NCH2C═CH2CH2), 2.43-2.39 (m, 1H, NCH2C═CH2CH2); 13C NMR (67.8 MHz, CDCl3) δ171.4 (NC═O), 151.0 (Cquat), 143.3 (Cquat), 141.5 (Cquat), 140.6 (Cquat), 136.5 (Cquat), 128.6 and 128.0 (BnC—Harom), 127.8 (Cquat), 127.1 (BnC—Harom), 112.5 (C—Harom), 107.8 (NCH2C═CH2), 103.0 (C—Harom), 70.6 (PhCH2O), 65.9 (NCHCH2OH), 60.0 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2); MS (EI), m/z (relative intensity) 368 (M+., 100), 353 (M—CH3, 2), 340 (1), 286 (2), 273 (4), 256 (M—NCH2C═CH2CH2CHCH2OH, 59), 249 (8), 226 (4), 200 (2), 196 (2), 166 (5), 138 (17), 112 (NCH2C═CH2CH2CHCH2OH, 39), 91 (PhCH2, 70), 82 (5), 65 (5); IR (NEAT) 3600-3000 (br, NH2 and OH), 3065, 3052, 2932, 2869, 2246, 1668, 1620, 1592, 1513, 1454, 1408, 1264, 1229, 1197, 1176, 1113, 1079, 1002, 909, 733, 698, 645 cm−1; exact mass calcd for C21H24N2O4 m/e 368.1736, obsd m/e 368.1662.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH2:45]>ClC(Cl)C>[F:14][C:15]([F:30])([F:29])[C:16]([OH:12])=[O:45].[F:30][C:15]([F:14])([F:29])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[O:26][C:25]([CH2:27][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)o1
Reactant: O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Reaction time: 12 h
Yield: 17 %

Procedure:
To a mixture of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.071 g, 0.401 mmol) in dichloroethane (3 mL) was added 5-[4-(trifluoromethyl)phenyl]-2-furancarbaldehyde (0.081 0.337 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.110 g, 0.519 mmol). The mixture was stirred for 7 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by preparative HPLC (10% to 100% CH3CN/H2O with 0.05% TFA) to give the title compound as a yellow solid (0.051 g, 17%). 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, J=8.2 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.06 (d, J=3.5 Hz, 1H), 6.87 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 6.42 (d, J=3.3 Hz, 1H), 4.29 (s, 2H), 2.20 (m, 1H), 1.59 (m, 1H), 1.29 (m, 1H), 1.19 (m, 1H). ES-MS m/z 400.02 (MH−).