Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([CH2:12][CH2:13][CH2:14][CH3:15])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(O)(C)(C)C.C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([N:41]=[N+:42]=[N-:43])=[O:10])=[CH:4][CH:3]=1
Reactant: CCCCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CCCCC(Cn1cncn1)(C(=O)N=[N+]=[N-])c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 42.5 %

Procedure:
To a stirred solution of 1.0 g (3.25 mmols) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexanoic acid in 3 mL of dimethylformamide was added 0.30 mL of tert-butanol. This solution was cooled to 0° C. and a solution of 1.07 g (3.90 mmols) of diphenylphosphorylazide in 1 mL of dimethylformamide was added followed by 0.72 mL (7.15 mmols) of triethylamine. The resultant mixture was stirred for 2 hours and then allowed to warm to room temperature and stirred for an additional 15 hours. Addition of ice caused the precipitation of the product. Filtration gave 1.10 g of a crude product which was carefully recrystallized from a 1 to 3 mixture of ethyl acetate and hexane to afford 0.46 g (47%) of azide as a white crystalline solid, melting point 100°-101° C.: 1H-NMR (CDCl3, Me4Si) 0.7-1.1 (t, J=6 Hz, CH2 --CH3), 1.1-1.7 (m), 1.75-2.1 (m), 4.6 (d, CH2 --N), 6.8-7.2(m,phenyl H), 7.3 (s,CH=N), 7.7 ppm (s,CH=N):
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CC(C)C[C@@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 86.8 %

Procedure:
3.78 g (8 mmoles) of Z-Glp-D-Leu-Pro-NH2 are dissolved in 150 ml of methanol, 0.8 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. The resulting 2.5 g of amorphous crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 2.35 g (87%) of Glp-D-Leu-Pro-NH2 are obtained; Rf4 =0.48, [α]D25 =-83.3° (c=1%, in acetic acid).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=[O:9])[CH2:7][CH2:6]2)[O:4][CH2:3]1.[Cl-].[NH4+].[CH2:17]([Mg]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:17]([C:8]1([OH:9])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][C:2]([CH3:14])([CH3:1])[CH2:13][O:12]2)[CH2:11][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1(C)COC2(CCC(O)(Cc3ccccc3)CC2)OC1
Reaction time: 2.5 h

Procedure:
To a solution of 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal (3.76 g) and zinc chloride (about 1.0 mol/L, solution in diethyl ether, 1.90 mL) in tetrahydrofuran (63.0 mL), benzylmagnesium bromide (about 1.0 mol/L, solution in tetrahydrofuran, 24.7 mL) was added at 0° C. and thereafter the mixture was stirred at that temperature for 2.5 hours. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added and three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to give 9-benzyl-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol as a colorless solid (1.28 g).
Reaction SMILES: C([NH:18][C:19]([C@@H:21]1[CH2:25][C@H:24]([F:26])[CH2:23][NH:22]1)=[O:20])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>C(NCC)C.ClCCl>[F:26][C@@H:24]1[CH2:23][NH:22][C@H:21]([C:19]([NH2:18])=[O:20])[CH2:25]1
Reactant: O=C(NC(=O)[C@@H]1C[C@H](F)CN1)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: ClCCl
Product: NC(=O)[C@@H]1C[C@H](F)CN1
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
(2S,4S)—N-Fmoc-4-fluoropyrrolidine-2-carboxamide (Fa) (354 mg, 1 mmol) was dissolved in 12 ml of a 1:1 mixture of diethylamine and dichloromethane at room temperature. After the mixture was stirred for 1.5 h, all the volatiles are removed. To the obtained residue was added ethyl acetate (10 ml) and water (5 mL), and the mixture was stirred and left. The aqueous layer was separated, washed with 10 ml of ethyl acetate, and evaporated to dryness by a vacuum pump. The residue was dissolved in 2 ml of isopropanol and mixed with ether. The precipitated solid was washed with ethyl acetate and dried in vacuo, giving 118 mg (yield 90%) of (2S,4S)-4-fluoropyrrolidine-2-carboxamide as crystals: 19F-NMR (D2O) δ −172.40 (m, 1 F): 1H-NMR (D2O) δ 2.0-2.5 (m, 2H), 2.95 (dd, 1H, J=38.8, 3.42 Hz), 3.20 (dd, 1H, J=21.6, 1.7 Hz), 3.0 (dd, 1H, J=10.3, 4.1 Hz), 5.16 (dt, 1H, J=53.2, 4.1 Hz): 13C-NMR (D2O) δ 37.52 (d, J=21.7 Hz), 52.68 (d, J=23.1 Hz), 58.49, 94.63 (d, J=171.2 Hz, 4-C), 177.71 (CO).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>O1CCCC1.CCCCCC>[CH2:11]([O:13][CH2:14][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:12]
Reactant: CCOCCl
Reactant: c1c[nH]cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCn1ccnc1
Temperature: -70 °C
Yield: 56.1 %

Procedure:
Imidazole (20 g) was dissolved in tetrahydrofuran (700 ml) under a nitrogen atmosphere, cooled to −70° C. and n-butyllithium (117.5 ml of a 2.5M solution in hexane) added dropwise, over 15 minutes. The mixture was allowed to warm to −20° C. and stirred at −20° C. for 30 minutes before the dropwise addition of chloromethyl ethyl ether (30.5 g). The mixture was allowed to warm to room temperature and stirred for a further hour. The solvent was removed under reduced pressure to give a residue which was triturated with dichloromethane and filtered through a short pad of Arbacel (trade mark) filter aid. The solvent was removed from the filtrate under reduced pressure to give a mobile oil which was distilled under reduced pressure (0.7 millibars, 0.53 mmHg) to give 1-ethoxymethylimidazole (20.8 g) as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:36])=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=3)[CH:27]=2)OC1>>[F:36][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(C#N)c3)c2)OC1
Product: N#Cc1cccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-3-carbonitrile as described in Example 65 to give 2′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-3-carbonitrile as a yellow solid: δH (360 MHz, CDCl3) 7.28 (1H, d, J 7), 7.40-7.46 (1H, m), 7.55-7.64 (3H, m), 7.72-7.75 (1H, m), 7.83 (1H, dd, J 7 and 1), 7.89 (1H, d, J 1), 8.11 (1H, s), 8.75 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: ClC1C=CC(F)(O)CC=1.[Cl:10][C:11]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH2:15][O:16]2>>[Cl:10][C:11]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:16][CH2:15][C:14]#[CH:13])[CH:12]=1
Reactant: Fc1ccc(Cl)c2c1OCC=C2
Agent: OC1(F)C=CC(Cl)=CC1
Product: C#CCOc1cc(Cl)ccc1F
Yield: 90 %

Procedure:
4-Chloro-1-fluoro-2-(2-propynyloxy)benzene was synthesized analogously to Example 33a from (4 g, 27 mmol) 4-chloro-1-fluorophenol to give 4.6 g of product (purified by column chromatography on silica, ethyl acetate/n-hexane 1:15) as yellow oil. Yield 90%. c) 5-chloro-8-fluoro-2H-chromene
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH2:4]O.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH2:4][Br:13]
Reactant: OCc1cc(F)c(F)cc1Br
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(Br)c(CBr)cc1F
Reaction time: 2 h
Yield: 120.7 %

Procedure:
To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid [prepared according to the procedure of Braish et al., Syn. Comm., 3067-3074 (1992)] in 75 mL of tetrahydrofuran was added 2.43 g (15 mmol) of carbonyldiimidazole. The solution was heated under reflux for 3.5 h, cooled to ambient temperature and 0.38 g (10 mmol) of sodium borohydride in 15 mL of water was added. The reaction was stirred for 10 min and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer was washed twice with warm water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.9 g of 2-bromo-4,5-difluorobenzyl alcohol. To a solution of 1.9 g (8.4 mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30 mL of dichloromethane at 0° C. was added 3.4 g (10 mmol) of carbon tetrabromide and 2.7 g (10 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 20:1 hexane:ethyl acetate) to afford 2.9 g of 2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromide which was used without further purification. Using the procedures outlined for the preparation of Intermediates 2-4, the benzyl bromide derivative was converted to the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([Br:13])=[CH:4][N:3]=1.[CH3:14][C:15]1([CH3:29])[CH2:23][C:22]2[NH:21][N:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[C:18]=2[C:17](=[O:28])[CH2:16]1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:21]3[C:22]4[CH2:23][C:15]([CH3:29])([CH3:14])[CH2:16][C:17](=[O:28])[C:18]=4[C:19]([C:24]([F:25])([F:27])[F:26])=[N:20]3)=[CH:9][CH:10]=2)[C:5]([Br:13])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)c2cc(F)ccc12
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)n[nH]c2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc4c(N)ncc(Br)c4c3)c2C1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To a solution of 1-amino-4-bromo-6-fluoro-isoquinoline (0.0395 g, 0.164 mmol) in DMF (1 mL) are added 6,6-Dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one (0.046 g, 0.2 mmol) and NaH (0.008 g, 0.2 mmol). The reaction mixture is microwaved at 120° C. for 40 min, cooled to RT, and treated with NH4Cl (satd. aq, 2 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (10% MeOH/CH2Cl2) affords 0.039 g (53%) of 1-(1-Amino-4-bromo-isoquinolin-6-yl)-6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one. LC/MS m/z=454 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]([C@@H:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24]1)=[O:22]>>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:31][C@H:23]3[C:21]([O:20][CH3:19])=[O:22])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1
Product: COC(=O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Yield: 81 %

Procedure:
Working in a manner similar to preparation IL, starting with the 4-(phenylmethoxy)benzenesulfonyl chloride and 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid methyl ester, the expected product is obtained in the form of a white powder with a yield of 81%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[CH2:14]([N:16](CC)[CH2:17]C)C.CNC>C1COCC1>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH2:2][N:16]([CH3:17])[CH3:14])[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CNC
Solvent: C1CCOC1
Product: COc1cc(CN(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a stirred solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 104, 0.2 g, 0.813 mmol) in dry THF (5 ml), was added triethylamine (0.1 g, 1 mmol) followed by a solution of dimethylamine in THF (0.5 ml of a 2M solution, 1 mmol). After stirring for 1 hour at room temperature, the solvent was removed in vacuum and the crude product was purified by silica gel column chromatography eluting with 10% methanol in ethyl acetate to afford the title compound as a white powder (0.16 g, 94%).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[O:18])=[CH:19][CH:20]=2)[N:6]=1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CN1CCN(C(=O)c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
A suspension of 4-(3-carbamoyl-6-chloropyridin-2-ylamino)benzoic acid (700 mg, 2.400 mmol), 1-methylpiperazine (288 mg, 2.88 mmol), HOBT (441 mg, 2.88 mmol), and EDC (552 mg, 2.88 mmol) in DMF (4 mL) was stirred at rt for 2 h. The reaction mixture was diluted with water and the resulting precipitate filtered and purified by MPLC chromatography (ISCO, solid loaded on CELITE®, 10% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 175 mg of 6-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)nicotinamide. LCMS: (M+H)+=374.05, 376.07 (Cl pattern); 1H NMR (400 MHz, CDCl3) δ ppm 10.74 (1H, s), 7.64 (3H, dd, J=8.13, 5.49 Hz), 7.21 (2H, d, J=8.79 Hz), 6.67 (1H, d, J=7.91 Hz), 3.38-3.97 (4 H, m), 2.34-2.59 (4H, m), 2.33 (3H, s), 1.70 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([O:19]C)[C:16]([O:21]C)=[C:15]([C:23]#[N:24])[C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([OH:19])[C:16]([OH:21])=[C:15]([C:23]#[N:24])[C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(C#N)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1c(O)c(O)cc2c(Cl)c(C(=O)N3CCOCC3)sc12
Temperature: -20 °C
Reaction time: 8 h

Procedure:
(3-Chloro-7-cyano-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (0.05 g) was suspended in dichloromethane under nitrogen, cooled to −20° C. and treated dropwise with a solution of 1M boron tribromide in dichloromethane. The suspension was stirred at −20° C. for 30 minutes and in cool overnight. The mixture was poured into ice-cold water and stirred at room temperature for 30 minutes. The product was filtered and purified by a preparative plate (reverse phase) using a mixture of toluene, ethyl acetate and acetic acid (8:1:1) as an eluent.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:29])=[O:28].[OH-].[NH4+:36]>O1CCOCC1>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccoc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (114 mg, 0.212 mmol) and ammonium hydroxide (4 mL) and 1,4-Dioxane (1 mL), the title compound was obtained as an off-white solid (82 mg, 70% yield). MS (ESI): 519 [M+H]+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].F[C:31]1[CH:36]=[CH:35][C:34]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:31]2[CH:32]=[CH:33][C:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])=[CH:35][CH:36]=2)[N:10]=[CH:9]1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 10 mmol of bis(4-fluorophenyl) sulphone are treated as described in Example 61 (method A).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:40]([Cl:41])=[C:39]([O:42][CH3:43])[CH:38]=[C:37]([O:44][CH3:45])[C:36]=3[Cl:46])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1)=O.[CH3:47][N:48]([CH3:53])[CH2:49][CH2:50][NH:51][CH3:52]>C(Cl)Cl.C(Cl)Cl.O>[CH3:47][N:48]([CH3:53])[CH2:49][CH2:50][N:51]([CH2:15][C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:36]([Cl:46])=[C:37]([O:44][CH3:45])[CH:38]=[C:39]([O:42][CH3:43])[C:40]=3[Cl:41])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1)[CH3:52]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1Cl
Reactant: CNCCN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN(C)CCN(C)C)c[nH]3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
Sodium triacetoxyborohydride (168 mg, 0.794 mmol, 3 equiv) was added to a suspension of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (125 mg, 0.265 mmol) (Example 179) and N,N,N′-trimethylethylenediamine (81 mg, 0.792 mmol, 3 equiv) in DCM (4 mL) at rt, under an argon atmosphere. The reaction mixture was stirred for 18 h at rt, diluted in DCM/H2O and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by trituration in Et2O to afford 88 mg of the title compound as a yellow solid: ES-MS: 558 [M+H]+; tR=3.14 min (System 1); TLC: Rf=0.05 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C1CCCCCCCCCCC1.N(OC(C)(C)C)=O.[CH2:20]([O:32]C(C1C=C2C(=O)N(O)C(=O)C2=CC=1)=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].S(=O)(=O)(O)O.[OH-].[Na+].C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>CCOCC>[C:20]1(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Agent: C1CCCCCCCCCCC1
Agent: CC(C)(C)ON=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=C1CCCCCCCCCCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Cyclododecane (3.32 g; 19.8 mmol), t-butyl nitrite (1 mmol), and 4-lauryloxycarbonyl-N-hydroxyphthalimide (0.5 mmol) were placed in a flask and were stirred at 70° C. in an atmosphere of argon gas for 2 hours. The resulting mixture was diluted with ether (2 ml) and was further treated with sulfuric acid having a concentration of 98% by weight (200 mg) with stirring at 70° C. for 15 minutes. The reaction mixture was then neutralized with sodium hydroxide and was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 58%, 5%, and 3%, respectively.
Reaction SMILES: Cl.Cl.Cl[C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][C@@H:24](O)[C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1.C=O>>[CH2:12]([N:15]1[CH2:16][CH2:17][C:12]2([C:6]3[C:7](=[CH:8][CH:9]=[CH:4][C:5]=3[CH2:22][NH:21][CH:20]([CH3:24])[CH3:19])[N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:11]2)[CH2:13][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Agent: C=O
Agent: Cl
Product: CC(C)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)CC2
Yield: 60 %

Procedure:
(R)—N-((1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (33 mg, 60%) was prepared by the procedures described in Example 18, substituting (R)-(1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine trihydrochloride trihydrochloride for (5R,7R)-4-(5-chlorospiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride, and substituting acetone for formaldehyde. LCMS (APCI+) m/z 482 [M+H]+; Rt=2.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ncc(Cl)cn2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(Cl)cn3)cc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyrimidin-2-yl)-phenol (Preparation 19) and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a white solid (153 mg, 65.7%)