Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8]Br)[CH3:2].[Na+].[I-].[H-].[Na+].[CH2:17]([OH:20])[CH2:18][OH:19]>O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][O:19][CH2:18][CH2:17][OH:20])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCBr
Reactant: OCCO
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)(C)CCCOCCO
Temperature: 70 °C
Reaction time: 20 h
Yield: 20 %

Procedure:
5-Bromo-2,2-dimethyl-pentanoic acid ethyl ester LVX (19 g, 74.5 mmol) was dissolved in ethylene glycol LXVI (150 mL) and stirred under argon. After NaI (1.13 g, 7.5 mmol) was added as a catalyst, NaH as a dispersion in mineral oil (3.0 g, 60%, in mineral oil; 75 mmol) was added slowly in five portions. After stirring for 20 min at rt, the mixture was subjected to gentle heating in an oil-bath to 70° C. After 20 h, the heating was discontinued and the mixture was cooled to rt. The reaction mixture was diluted with H2O (500 mL), then extracted with chloroform (5′ 100 mL). The chloroform extract was then washed with 10% aq Na2S2O3 (300 mL), then with H2O (400 mL). After drying over MgSO4, the solvent was evaporated to give crude product (13.1 g), which was further purified by vacuum distillation (80-83 C., 0.11 torr) to give the desired product (3.25 g, 20% yield) as a clear, colorless oil. 1H NMR (CDC13), d (ppm): 4.51 (t, 1 H, J=5.5); 4.05 (q, 2 H,J=7.1); 3.48 (m, 2H); 3.40-3.31 (m, 4H); 1.18 (t, 3 H,J=7.1); 1.11 (s, 6H). 13C NMR (CDCl3), d (ppm): 176.7, 72.0, 70.5, 60.3, 59.8, 41.3, 36.7, 24.88, 24.78, 14.0. HRMS calcd. for C11H23O4 (MH+): 219.1613, found 219.1605.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:18])[C@H:6]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:5]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:3])[CH3:2].O([CH2:40][CH2:41][O:42][CH3:43])S(C(F)(F)F)(=O)=O.[H-].[Na+]>ClCCl.CN1CCCC1=O>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:40][CH2:41][O:42][CH3:43])[C@H:6]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:5]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: COCCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)N1c2c(ccn3cc(C)nc23)[C@@H](O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COCCO[C@@H]1c2ccn3cc(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
To a of −30° C. cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in dichloromethane (25 ml) and N-methyl-pyrrolidinone (25 ml) is added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40 g (35.2 mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate/cyclohexane/triethylamine: 5/4/1) to give 7.50 g (15.63 mmol/89%) of the title compound as a yellow amorphous solid. 1H-NMR (200 MHz,[D6] DMSO): δ=1.19 (s, 9H), 2.15 (s, 3H), 2.38 (s, 3H), 3.27 (s, 3H), 3.45-3.57 (m, 2H), 3.83-3.93 (m, 2H), 4.60 (d, 1H), 5.31 (t, 1H), 5.79 (d, 1H), 6.94 (s, 1H), 7,20 (s, 5H), 7.74 (s, 1H), 8.43 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:8]=1)([O-])=O.[H][H]>[Pd].CO>[S:9]([N:7]1[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2cc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(N)cn2)cc1
Yield: 71.5 %

Procedure:
4-nitro-1-tosyl-1H-pyrazole (example 9-1c) (3 g, 11.2 mmol) and 10% palladium on carbon (800 mg) in MeOH (150 mL) were stirred under 2 atmospheres of hydrogen on the Parr hydrogenator for 3 hours. The mixture was filtered through celite, concentrated and purified by silica gel chromotography (80% ethyl acetate in hexanes) to afford 1-tosyl-1H-pyrazol-4-amine (1.9 g, 71%) as a pink solid. 1H NMR (CDCl3, 400 MHz), 2.40 (s, 3H), 3.01 (bs, 2H), 7.29 (d, 2H, J=8 Hz), 7.41 (d, 1H, J=1.2 Hz), 7.53 (d, 1H, J=1.2 Hz), 7.81 (d, 2H, J=8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2)#[CH:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]3)[CH:16]=1
Reactant: C#Cc1ccc2c(c1)CCC(=O)N2
Reactant: Brc1cccnc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1CCc2cc(C#Cc3cccnc3)ccc2N1

Procedure:
A mixture of 11.6 mg of cuprous iodide, 86 mg of bis (triphenylphosphine)palladium(II)dichloride, 1.0 g of 6-ethynyl-3,4-dihydrocarbostyril and 3-bromopyridine were reacted as shown in Example 9, and the product isolated in a similar fashion, giving 6-[2-(3-pyridyl)ethynyl]-3,4-dihydrocarbostyril, m.p. 195°-197° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)C.[CH3:7][Si:8]([CH3:23])([CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[CH2:16][O:15]1>O>[CH3:1][N:2]([CH3:3])[CH2:16][CH:14]([OH:15])[CH2:13][O:12][CH2:11][CH2:10][CH2:9][Si:8]([CH3:23])([CH3:7])[CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CNC
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: O
Solvent: CCO
Product: CN(C)CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C
Temperature: 50 °C

Procedure:
Aqueous dimethylamine (25%; 10 g, dimethyl amine ˜55 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 50° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 50° C. for an additional 8 hours. Ethanol, water and excess dimethyl amine were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].CN(C)C=O.Cl[CH:39]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42][CH2:43][CH3:44])=[O:41].[F-].[K+]>C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([O:26][CH:39]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:25])[CH2:22][C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)O
Reactant: CCOC(=O)C(Cl)OC(=O)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(=O)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(CCCCc1ccccc1)OCC)OC(=O)C(C)(C)C
Reaction time: 48 h

Procedure:
A solution of 2.0 g. of (+)-4,5-dihydro-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, from Example 1(c), in 30 ml. of dry dimethylformamide under argon at room temperature is treated with 1.2 g. of ethyl 2-chloro-2-pivaloyloxyacetate, from part (a), and 0.58 g. of anhydrous potassium fluoride. After stirring for 48 hours the mixture is diluted with ethyl acetate and washed with water (3×). The organic fraction is dried (MgSO4) and concentrated in vacuo to give crude product. Flash chromatography on silica gel and elution with acetone/hexane (2:1) gives homogeneous (+)-4,5-dihydro-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, 1-(2,2-dimethyl-1-oxopropoxy)-2-ethoxy-2-oxoethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2S(C1C=CC(O)=C(C)C=1)(=O)=O.[CH3:28][O:29][C:30]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:30]=1[O:29][CH3:28]
Reactant: CCC1c2cccn2-c2ccc(Cl)cc2N1S(=O)(=O)c1ccc(O)c(C)c1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: CCC1c2cccn2-c2ccc(Cl)cc2N1C(=O)c1ccc(OC)cc1OC

Procedure:
7-Chloro-5-(2,4-dimethoxybenzoyl)-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the intermediate of Example 68A and 2,4-dimethoxy benzoyl chloride according to the procedure of Example 106, Step 2 mp 70-74° C. MS (ESI) m/z 397; Anal. Calcd for C22H21ClN2O3: C, 66.58; H, 5.33; N, 7.06. Found: C, 66.34; H, 5.59; N, 6.85.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:28][CH:24]([CH2:25][CH2:26][CH3:27])[CH:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(OS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., triethylamine (0.300 ml, 2.16 mmol) and methanesulfonyl chloride (0.150 ml, 1.93 mmol) were added to a methylene chloride (10 ml) solution of the 1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol (449 mg, 1.20 mmol) obtained in Example 11. The resulting mixture was then stirred at 0° C. for 2 hours. The reaction mixture was diluted with methylene chloride, washed successively with a saturated aqueous solution of ammonium chloride, water and brine, dried over MgSO4, then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (15% ethyl acetate-hexane), whereby the title compound (503 mg, 93%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Li+].[CH3:27]C([N-]C(C)C)C.CI>C1COCC1>[Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:27]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(Cl)oc12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Cl)oc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
Di-tert-butyl (2-chlorofuro[2,3-c]pyridin-7-yl)imidodicarbonate (3.0 g, 8.15 mmol) in dry THF (100 mL) was cooled to −65° C. to −75° C. and LDA (1.8 M in THF/heptanes/ethylbenzene, 6.0 mL, 10.8 mmol), pre-cooled to the same temperature, was added slowly via syringe over a period of 10 min. The mixture was stirred for 1.5 h at −65° C. to −75° C. and then treated with methyl iodide (0.76 mL, 12.2 mmol) in dry THF added slowly via syringe. The mixture was allowed to warm to RT overnight and was quenched by the addition of water (50 mL) and diluted with EtOAc (100 mL). The phases were separated and the organic phase was dried over Na2SO4, and concentrated in vacuo leaving 3.2 g of a brown solid which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=5.5 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 2.22 (s, 3H), 1.40 (s, 18H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])[NH:20][C:19]=1[CH:32]=O>>[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])[NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-methyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[C:12](=O)[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-]S([O-])(=O)=O.[Na+].[Na+].[C@@H:25]1([NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH2:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[C@@H:12]([NH:31][C@@H:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]2[NH2:32])[CH2:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CC2CC1N(c1ccc([N+](=O)[O-])cc1)C2
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N[C@@H]1CCCC[C@H]1N[C@H]1CC2CC1N(c1ccc([N+](=O)[O-])cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a round bottom flask was added 2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-one (120 mg, 0.517 mmol), CH2Cl2 (3 mL) and Na2SO4 (5 gms). The reaction was purged with argon. Then (1R,2R)-cyclohexane-1,2-diamine (118 mg, 1.033 mmol) and acetic acid (0.592 mL, 10.33 mmol) were added to the reaction. The reaction was stirred at rt for 1 hr. After this time, sodium triacetoxyborohydride (548 mg, 2.58 mmol) was added to the reaction and the reaction was stirred at rt overnight. The reaction was diluted with CH2Cl2 (50 ml) and filtered. The organic layer was washed with 0.5N NaOH (30 ml), water (30 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC. Two isomers were separated from RP prep-HPLC. The fractions with the desired product, which eluted later than the undesired isomer, were concentrated to give (1R,2R)—N1-((6S)-2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-yl)cyclohexane-1,2-diamine (80 mg, 0.242 mmol, 46% yield) as a yellow solid. Anal. Calcd. for C18H26N4O2 m/z 330.4, found: 331.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:20])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12]3)[CH:5]=[CH:4][C:3]=1[NH2:21].[F:22][C:23]([F:28])([F:27])[C:24](O)=O>>[CH2:14]([N:11]1[CH2:10][CH:9]2[CH:13]([C:8]2([C:6]2[CH:5]=[CH:4][C:3]3[NH:21][C:24]([C:23]([F:28])([F:27])[F:22])=[N:1][C:2]=3[CH:7]=2)[CH3:20])[CH2:12]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc(N)c(N)c1
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc2[nH]c(C(F)(F)F)nc2c1
Yield: 54 %

Procedure:
A solution of 2-amino-4-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 48, 99.0 mg, 0.345 mmol) in trifluoroacetic acid (2.0 ml) was heated under reflux for 1 hour. The mixture was cooled and the solvent was removed in vacuo. The residue was suspended in 2N sodium hydroxide (5 ml) and the aqueous layer was extracted with diethyl ether (3×5 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography eluting with ethyl acetate to afford the title compound (67 mg, 54%) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C@@H:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][C@H:33]([CH3:32])[CH:34]([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)[C@@H](C)N
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: CC(C)[C@@H](C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 13 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (R)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1, 2) gave 30 mg (13%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH2:3]1.Cl>C(O)C.O.[Fe]>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc([N+](=O)[O-])c1)N2
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Yield: 50.1 %

Procedure:
To a stirred solution of 4,4,6-Trimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (10 g) in Ethanol/water (150 mL/30 mL) was added concentrated hydrochloric acid (2 mL) and Iron Powder (20 g, 356 mmol). The resultant mixture was heated to reflux for 2 h. Iron Powder was filtered, and washed with ethanol. The combined filtrate was concentrated, and diluted with water. The mixture was extracted with ethyl acetate (250 mL×3). The combined organic layers were washed with saturated brine, and the brine was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, concentrated. The residue was treated with ether and hexane to afford 4.5 g of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine as brown solid (Yield: 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH2:15](OS(C)(=O)=O)[C:16]#[C:17][CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:15]([O:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:16]#[C:17][CH3:18]
Reactant: CC#CCOS(C)(=O)=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#CCOc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 12 h

Procedure:
2-nitro-4-trifluoromethyl-phenol 7 (4.1 g, 20 mmol) and methanesulfonic acid but-2-ynyl ester 20 (3.0 g, 20 mmol) are dissolved in MeCN. Cs2CO3 is added (13.0 g, 40 mmol) and the mixture is stirred at 90° C. for 12 hours. The mixture is then filtered, concentrated in vacuo, diluted with H2O and extracted three times with DCM. The organic layers are combined, dried (MgSO4), filtered, and concentrated and the remainder purified by column chromatography using a hexanes/EtOAc gradient to afford 1-but-2-ynyloxy-2-nitro-4-trifluoromethyl-benzene 21 as a yellow solid: 1H-NMR (400 MHz, CDCl3) δ=8.06 (d, J=1.7 Hz, 1H), 7.73 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 4.81 (q, J=2.3 Hz, 2H), 1.79 (t, J=2.3 Hz, 3H). MS calculated for C11H9F3NO3 (M+H+) 260.1, found 260.3.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10]1([CH2:16][C:17](P(=O)(OCC)OCC)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][C:17]([N:1]2[CH2:9][CH2:8][N:7]([C:17](=[O:18])[CH2:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5][N:4]([C:17](=[O:18])[CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:3][CH2:2]2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOP(=O)(OCC)C(=O)Cc1ccccc1
Reactant: C1CNCCNCCN1
Product: O=C(Cc1ccccc1)N1CCN(C(=O)Cc2ccccc2)CCN(C(=O)Cc2ccccc2)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), diethyl phenylacetylphosphonate [PhCH2COP(O)(OEt)2].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC(N(C)C)=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: BrC1CCCC1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCCC1
Reaction time: 8 h

Procedure:
4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 15) (0.91 g) in 50 mL dry dimethylacetamide was stirred under nitrogen at 25° C. while adding 60% sodium hydride (0.20 g). After stirring for 30 minutes bromocyclopentane (0.8 mL) was added and the mixture stirred overnight. After evaporation in vacuo the residue was treated with water and extracted into ethyl acetate. Flash chromatography (3:2 cyclohexane:ethyl acetate) eluted 0.36 g of 1-cyclopentyl-4-(cyclopentylamino)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine as colourless oil. 1H n.m.r. (DMSO) 8.319 (s, 1H), 7.65-7.69(m,2H), 7.40-7.48(m,2H), 7.09-7.23(m,5H), 5.926/5.955(d,1H), 5.17-5.29(quin, 1H), 4.44-4.52(m,1H), 1.86-2.12(m,8H),1.39-1.72(m,8H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(=O)C1C=CC([O:18]C)=CC=1.O1CCCC1.ClC1C=C(C=CC=1)C(OO)=O>C(OC)(C)(C)C>[OH:18][NH:10][C@@H:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@H](CO)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: OC[C@@H](NO)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-phenylglycinol (15 g) and p-anisaldehyde (16.4 g) in methyl tert-butyl ether (150 mL) was heated to reflux, with a Dean-Stark trap attached, for about 3 hours. Tetrahydrofuran (60 mL) was added and the mixture cooled to 0° C. To this was added a solution of m-chloroperoxybenzoic acid (29.8 g) in methyl tert-butyl ether (80 mL), maintaining the temperature below 5° C. The mixture was stirred at 0° C. for about 3 hours. Then the reaction mixture was washed with 10% aqueous potassium carbonate (3×75 mL). The resulting organic layer was concentrated to a smaller volume. To this was added a solution of hydroxylamine hydrochloride (15.3 g) in methanol (19 mL) and water (27 mL), and the reaction was stirred at room temperature for about 3 hours. Heptane (30 mL) and water (30 mL) were added. The layers were separated, and the aqueous layer was washed with methyl tert-butyl ether (3×30 mL). The methanol was removed by vacuum distillation, and then methyl tert-butyl ether (75 ml) was added. After adjusting the pH to 7 with solid potassium carbonate, sodium chloride was added and the layers separated. The aqueous layer was further extracted with methyl tert-butyl ether (2×75 mL). The combined methyl tert-butyl ether extracts were filtered, concentrated to a small volume, and then heptane (70 mL) was added. The resulting slurry was stirred at room temperature for about 1 hour and then cooled to 0° C. After stirring for 1 hour, the mixture is filtered and the wetcake washed with heptane (20 mL). The wetcake was then dissolved in dichloromethane (100 mL) for use in the next step. 1H NMR (400 MHz, CDCl3) δ 3.83–3.91 (2H, m), 4.12 (1H, dd, J=6.9, 4.8 Hz), 4.84 (3H, br s), 7.27–7.36 (5H, m). 13C NMR (100 MHz, CDCl3) δ 63.8, 67.7, 127.5, 127.9, 128.4, 137.5.