Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10]Br>CC(O)=O>[Br:10][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: Nc1cccc(F)c1F
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,3-difluoroaniline (20 g, 154.9 mmol) in HOAc (230 mL) was added over 1 hour a solution of bromine (24.75 g, 7.978 mL, 154.9 mmol) in HOAc (70 mL) at RT. The reaction mixture was stirred at RT for another 1 hour and a white precipitate appeared. The solvent was removed under reduced pressure, the residue was made basic with 6M NaOH at 0° C., and the basic solution was extracted with DCM. After drying the organics over MgSO4, the volatiles were removed in vacuo to provide 4-bromo-2,3-difluoroaniline (Compound 1079); LC/MS (M+H)=207.96. This compound was reacted with the acyl chloride of 2-fluoronicotinic acid and carried through the sequence of reactions as described in Example 19 to produce N-tert-butyl-3-(1-(4-bromo-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1080); 1H NMR (300 MHz, DMSO-d6): δ 8.21 (dd, J=1.9, 4.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.54-7.48 (m, 1H), 7.44 (dd, J=1.9, 7.7 Hz, 1H), 6.71 (s, 1H), 6.58 (dd, J=4.8, 7.7 Hz, 1H) and 1.31 (s, 9H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C@H:9]1[C@H:37]([CH3:38])[C@@H:36]2[C@@:12]([C:40]([OH:42])=[O:41])([CH2:13][CH2:14][C@@:15]3([CH3:39])[C@:20]4([CH3:35])[CH2:21][CH2:22][C@H:23]5[C@@:28]([CH2:30][OH:31])([CH3:29])[C@@H:27]([OH:32])[C@H:26]([OH:33])[CH2:25][C@:24]5([CH3:34])[C@H:19]4[CH2:18][CH:17]=[C:16]32)[CH2:11][CH2:10]1>N1C=CC=CC=1>[CH3:8][C@H:9]1[C@H:37]([CH3:38])[C@@H:36]2[C@@:12]([C:40]([OH:42])=[O:41])([CH2:13][CH2:14][C@@:15]3([CH3:39])[C@:20]4([CH3:35])[CH2:21][CH2:22][C@H:23]5[C@@:28]([CH2:30][O:31][C:30]([CH3:28])=[O:31])([CH3:29])[C@@H:27]([O:32][C:27]([CH3:26])=[O:32])[C@H:26]([O:33][C:5]([CH3:6])=[O:7])[CH2:25][C@:24]5([CH3:34])[C@H:19]4[CH2:18][CH:17]=[C:16]32)[CH2:11][CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12
Solvent: c1ccncc1
Product: CC(=O)OC[C@@]1(C)[C@@H]2CC[C@]3(C)[C@H](CC=C4[C@@H]5[C@@H](C)[C@H](C)CC[C@]5(C(=O)O)CC[C@]43C)[C@@]2(C)C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 10 °C

Procedure:
With reference to the first step in scheme 7 above, asiatic acid (5 g) was dissolved in pyridine (10 ml) with stirring. The solution was cooled down to 10° C., and 15 ml of acetic anhydride were added. The resultant solution was stirred at room temperature for 20 hours, and then 200 ml of ice water were added. A precipitate formed, was filtered out and washed with water, and then was dried under 50° C. to yield 6.28 g of asiatic acid triacetate as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:18]=2)[CH:14]=1)[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([CH:3]([CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:18]=2)[CH:14]=1)[CH2:4][C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])=[O:1]
Reactant: Cc1cc(CC(CO)CC(=O)OC(C)(C)C)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(CC(C=O)CC(=O)OC(C)(C)C)cc2cn(COCC[Si](C)(C)C)nc12

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)-4-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)butanoate (0.5500 g, 1.27 mmol) in methylene chloride (25 mL) was added Dess-Martin reagent (0.6449 g, 1.52 mmol) at room temperature. The reaction was stirredo vernight before washing with 1 N sodium hydroxide (10 mL) and water (2×10 mL). The organic layer was dried, filtered and concentrated. The final product was obtained by flash chromatography using 0% to 50% ethyl acetate/hexane (0.2773 g, 51%) HPLC tR=2.02 min, 1H-NMR (400 MHz, CDCl3) δ 9.42 (1H, s), 7.94 (1H, s), 7.19 (1H, s), 6.82 (1H, s), 5.64 (2H, s), 3.57 (2H, t, J=8.40 Hz), 3.02 (2H, m), 2.58 (1H, m), 2.54 (3H, s), 2.49 (1H, m), 2.30 (1H, m), 1.33 (9H, s), 0.87 (2H, t, J=8.40 Hz), −0.01 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]([O:18][CH3:19])=[C:8]([N:4]2[CH:5]=[N:6][C:2]([CH3:1])=[N:3]2)[CH:13]=1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1F
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(F)cc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 18.6 %

Procedure:
Step B (1): A mixture of 3-methyl-1H-1,2,4-triazole (2.20 g, 26.4 mmol), 1,5-difluoro-2-methoxy-4-nitrobenzene (5.00 g, 26.4 mmol), and potassium carbonate (3.65 g, 26.4 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 500 mL of water/10 mL brine solution. The aqueous mixture was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (50% EtOAc/hexane) to afford 1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.24 g, 18% yield). LC-MS (M+H)+=253.2. 1H NMR (500 MHz, chloroform-d) δ ppm 8.95 (s, 1 H) 8.00 (d, J=11.60 Hz, 1 H) 7.80 (d, J=6.10 Hz, 1 H) 4.09 (s, 3 H) 2.50 (s, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=1)[CH:7]=[O:8].[OH-].[Na+]>CO>[OH:27][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:17]=[CH:16]/[C:12]1[N:11]=[C:10]([NH:9][CH:6]([CH:7]=[O:8])[CH2:5][CH2:4][C:3]([OH:28])=[O:2])[CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(NC(C=O)CCC(=O)OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(NC(C=O)CCC(=O)O)n1
Yield: 69.2 %

Procedure:
Under the conditions of example 2, 60 mg of 4-{6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridylamino}-5-oxo-pentanoic acid methyl ester in 1.5 ml of methanol is saponified with 1.5 ml of 1 n sodium hydroxide solution and worked up. 40 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:28].[OH:29]O>>[Br:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:29])=[CH:13][C:5]2[C:6]([CH3:11])([CH3:12])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:28]
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc3c(c(Br)c2Br)NC(=O)OC3(C)C)cc1
Product: Cc1ccc(S(=O)CCCCOc2cc3c(c(Br)c2Br)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 7,8-dibromo-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)CCC>[C:1]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: [H][H]
Solvent: CCCCO
Product: CCCCOC(=O)CCC

Procedure:
Further n-butyraldehyde is supplied to nozzle 123 in second vaporiser 122 by way of line 124. Reference numeral 125 indicates a distribution tray. A hot vaporous mixture comprising unreacted hydrogen from first catalytic stage 116, product n-butanol, inerts, and a minor amount of by-products, e.g. n-butyl n-butyrate, also formed in first catalytic stage 116, exits vaporiser 122 overhead in line 126 at a temperature of 105° C. After passage through a heater 127, supplied with a suitable heating medium, e.g. steam, in line 128, the mixture passes on in line 129 at a temperature of 125° C. to second catalytic stage 130. The aldehyde is quantitatively hydrogenated, n-butanol being the major product, under adiabatic conditions. The temperature of the vaporous reaction mixture exiting second catalytic stage 130 in line 131 is 195° C. After heat recovery in heat exchanger 132 by indirect heat exchange with a cooling medium, e.g. boiler feed water, supplied in line 133, the reaction mixture, now at 150° C. passes on in line 109 to heat exchanger 108.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Yield: 83 %

Procedure:
To a degassed solution of 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (270 mg, 1.0 mmol), 4-fluorobenzeneboronic acid (155 mg, 1.0 mmol), 2N Na2CO3 (1.5 mL) in DME (10 mL) was added tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) under argon. The mixture was heated to 85° C. for 6 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% methylene chloride in heptane) to give the product as an off white solid (275 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=7.91 Hz, 2H), 8.12 (dd, J=5.27, 9.04 Hz, 2H), 7.74 (d, J=8.29 Hz, 2H), 7.54 (d, J=3.01 Hz, 2H), 7.18 (t, J=8.67 Hz, 2H), 2.50 (s, 3H). MS m/e 332.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[CH2:18]([OH:21])[C:19]#[CH:20]>C(NCC)C>[OH:21][CH2:18][C:19]#[C:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: C#CCO
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Solvent: CCNCC
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCO
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 0.37 g (0.5 mmole) of dichlorobis (triphenylphosphine) palladium II, 70 mg (0.35 mmole) of cuprous iodide, 36.1 g (0.1 mole) of 5-chloro-2'-fluoro-2-iodobenzophenone and 12 ml (0.2 mole) of propargyl alcohol in 200 ml of diethylamine was stirred at room temperature for 4 days. The mixture was concentrated at reduced pressure and the residue was partitioned between ether and water. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give the product as an amber oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[N+:24]([O-])=O)[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[NH2:24])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1N
Yield: 99.3 %

Procedure:
(2-benzylamino-3-nitro-6-trifluormethyl-pyridin-4-yl)-carbamic acid ethyl ester (95 mg, 0.25 mmol) was dissolved in 10 mL of ethanol and Raney Nickel (20 mg, 20% MW) was added then the reaction mixture was stirred at room temperature in a bomb under 50 PSI of hydrogen for 2 h. The mixture was filtered through arbocel and the filtrate was concentrated in vacuo to give 88 mg of the title compound as a pale green gum.
Reaction SMILES: [OH:1][C@H:2]([C@@H:11](O)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][C@@H:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1.CCOCC>[Br:36][C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:2]([OH:1])[CH2:3][C@@H:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](O)[C@@H](O)C[C@H](C(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)C[C@@H](Br)[C@@H](O)C[C@H](C(=O)O)C(C)C
Reaction time: 0.5 h

Procedure:
A stirred solution of the γ-lactone of (2S,4S,5S)-4,5-dihydroxy-2-isopropyl-7-methyloctanoic acid from Preparation IIIA (0.214 g., 1 mmol) and triphenylphosphine (0.289 g., 1.1 mmol) in benzene (3 ml) is cooled in an ice bath and treated during 5-10 minutes with N-bromosuccinimide (0.196 g., 1.1 mmol). The mixture is kept cold for an additional 30 minutes and then at ambient temperature for 4 hours. It is diluted with Et2O and filtered. The filtrate is con-centrated and the residue chromatographed on silica gel (100 g.) with 7.5% EtOAc-hexane. The product, the γ-lactone of (2S,4S,5R)-5-bromo-4-hydroxy-2-isopropyl-7-methyloctanoic acid, thus obtained was crystallized from cold pentane to give 0.061 g., m.p. 62.5°-63.5° C. and 0.054 g., m.p. 60°-62.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[CH3:21][NH2:22].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10](=[O:20])[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:22]1[CH3:21]
Reactant: Cc1ccccc1C=CC(=O)C=Cc1ccccc1C
Reactant: CN
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CC(=O)CC(c2ccccc2C)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
1,5-Bis(2-methylphenyl)-1, 4-pentadien-3-one (20ac, 0.50 g, 1.9 mmol) was dissolved in dimethyl formamide (10 ml). Methylamine (51, 1.0 ml, 11.6 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.29 g (52%) of a white solid: mp 155-157° C.; 1H NMR δ 1.82, (s, 3H), 2.40, (s, 6H), 2.44 (d, 2H, J=11.9 Hz), 2.77 (t, 2H, J=13.3 Hz), 3.74 (d, 2H, J=11.9 Hz), 7.16 (m, 6H), 7.67, (d, 2H, J=7.0 Hz); 13C NMR: δ 19.5, 39.9, 49.3, 65.8, 126.7, 126.9, 130.6, 134.8, 140.9, 207.2; Exact mass calcd for C20H23NO: 293.1779, observed (M+H) 294.1856.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]1[CH:11]=[C:12]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:13]=[C:14]([F:18])[C:15]=1[S:16][CH3:17]>C(O)C.O>[F:9][C:10]1[CH:11]=[C:12]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:2][OH:3])[CH:13]=[C:14]([F:18])[C:15]=1[S:16][CH3:17]
Reactant: CSc1c(F)cc(CC(=O)c2ccccc2)cc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1c(F)cc(CC(=NO)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
Hydroxylamine hydrochloride (5.5 g, 0.079 mol) and sodium acetate (6.5 g, 0.079 mol) were added to a slurry of 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone in ethanol (120 mL) and water (30 mL). The mixture was heated and held at reflux for 1 hour, then cooled and allowed to stir for 18 hours at room temperature. Additional water (50 mL) was added, and the mixture concentrated to half its volume. Dilute HCl was added, and the mixture extracted with dichloromethane (1×100 mL), 3×50 mL). The combined extracts were washed with dilute sodium bicarbonate, dried with magnesium sulfate, and concentrated to give a light yellow oil, that was crystallized from ethyl acetate/hexanes to afford 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone oxime as white solid (6.2 g, 53%). A second crop (2.3 g, 73% net yield) was also collected. 1H NMR (CDCl3/400 MHz) 7.57-7.60 (m, 2H), 7.35-7.37 (m, 3H), 6.80-6.84 (m, 1.7H), 6.75-6.77 (m, 0.3H), 4.14 (s, 1.7H), 3.83 (s, 0.3H), 2.39 (s, 3H). HRMS m/z 244.0773 (M+H+, calcd 244.0764). Anal. Calcd for C15H13F2NOS: C, 61.42; H, 4.47; N, 4.78. Found: C, 61.44; H, 4.50; N, 4.84.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][CH3:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:17].[CH:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>O1CCOCC1>[CH2:15]([CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:25]([C:24]4[CH:28]=[CH:29][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=4)[O:17][C:3]=3[CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1)[CH3:16]
Reactant: CCC1CC(=O)NN=C1c1ccc(N)c(O)c1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C(C)C)cc3)oc2c1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
200 mg (857 μmol) 6-(4-amino-3-hydroxy-phenyl)-5-ethyl-4,5-dihydro-2H-pyridazin-3-one are placed in 5 ml dioxane. 175 mg (958 μmol) 4-isopropyl-benzoyl chloride are added and the mixture is stirred for 15 min at 200° C. in the microwave. The solvent is eliminated by rotary evaporation in vacuo and the residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:22])=[CH:4][N:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:38][C:39]1[CH:52]=[CH:51][C:42]2[NH:43][C:44](=[O:50])[CH2:45][CH2:46][C:47]([CH3:49])([CH3:48])[C:41]=2[CH:40]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:38][C:39]2[CH:52]=[CH:51][C:42]3[NH:43][C:44](=[O:50])[CH2:45][CH2:46][C:47]([CH3:49])([CH3:48])[C:41]=3[CH:40]=2)=[N:3][CH:4]=1
Reactant: CCN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN([C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl)S(C)(=O)=O
Temperature: 120 °C

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-ethyl-methanesulfonamide (99 mg, 0.27 mmol) in Isopropyl alcohol (4 mL) was added to 10-Camphorsulfonic acid (12 mg, 0.052 mmol) and 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (56 mg, 0.27 mmol) and was heated in a Microwave vial for 90 min at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo onto Celite. Chromatography (ISCO, 12 g silica gel, 40-80% EtOAc:Hex) afforded N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-ethyl-methanesulfonamide as an off white foam (78 mg, 54%). LCMS: 535 (M+H); 1H-NMR, CDCl3: 7.91 (s, 1H), 7.74 (d, 1H, J=8.5 Hz), 7.34 (s, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 6.88 (d, 1H J=8.5 Hz), 6.02 (d, 1H, J=8.2 Hz), 3.99 (m, 1H), 3.75 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 2.92 (s, 3H), 2.45 (m, 1H), 2.40 (t, 2H, J=7.0 Hz), 2.13 (t, 2H, J=7.0 Hz), 1.95 (m, 2H), 1.44 (s, 6H), 1.39 (m, 3H), 1.16 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[CH2:24]([Li])CCC.S(OC)(OC)(=O)=O>C1COCC1>[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH:6]([CH3:24])[CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1
Reactant: [Li]CCCC
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CC1CC(c2ncc3nccc-3[nH]2)C(C)C(c2ccccc2)N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A suspension of 2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyridine (Example 35) (57 mg, 0.20 mmol) in THF (3 mL) was placed under a N2 atmosphere and cooled with a dry-ice bath to −78° C. n-Butyl lithium (Aldrich Chemical Company) (360 μL, 0.90 mmol, 4.5 equiv of a 2.5 M solution in hexanes) was added slowly. The reaction mixture was stirred at −78° C. for 1 h and allowed to warmed to 0° C. Dimethyl sulfate (Eastman Kodak Company) (73.8 mg, 0.60 mmol, 3.0) was added slowly at 0° C. The solution was allowed to warm to room temperature and stir overnight. The reaction was quenched by the addition of 10% NH4Cl (3 mL) and the THF was evaporated under reduced pressure. The solution was extracted with CHCl3 (3×50 mL), and the combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-20%):hexanes(100-80%) to provide 20 mg (34%) of the title compound as a white solid [30 mg (53%) of recovered starting material was also obtained]. Mp: 131-132° C. 1H NMR (acetone-d6, 400 MHz): δ 7.68 (d, 2, J=7.0), 7.54 (t, 2, J=7.0), 7.47 (t, 1, J=7.0), 3.84 (s, 3), 3.40 (t, 4, J=4.9), 2.50 (s, 3), 1.78 (m, 4), 1.70 (m, 2). MS m/z: 307 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([F:23])=[CH:15][C:14]=1[CH2:24][CH2:25][CH:26]=O>>[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[C:16]([F:23])=[CH:15][C:14]=1[CH2:24][CH2:25][CH:26]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1cc(F)c(C(F)(F)F)cc1F
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(C(F)(F)F)cc1F

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (6.340 mmol) and 3-(2,5-difluoro-4-trifluoromethyl-phenyl)-propionaldehyde (1.509 g; 6.340 mmol) afforded 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.79 min.; [M+H]+=485.87 g/mol. Subsequent protection of the secondary amine, and purification by FC (DCM/MeOH=50/1) allowed the isolation of the pure product 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a slightly beige solid (1.890 g; 51%). LC-MS: tR=0.99 min.; [M+H]+=585.78 g/mol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:8]=1)#[N:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: COCOc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1cc(C#N)ccc1N
Yield: 58.5 %

Procedure:
A mixture of 5-cyano- 1 -methoxymethyloxy-2-nitrobenzene (0.5 g, 2.4 mmol) and 10% palladium on carbon (.05 g) in ethyl acetate (50 mL) was stirred at rt under 1 atm of hydrogen for 72 h. The mixture was filtered through Celite to remove the palladium and the residue was chromatographed on silica gel (eluting with 25% ethylacetate/hexane) to afford the title compound (250 mg, 58%). MS(ES+) m/e 179 [M+H]+