Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([F:31])[CH:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3F)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
572 mg (8.78 mmol) of potassium cyanide were added to 1.94 g (4.39 mmol) of the compound from Example 54A in 26 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.30 g (79% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:72][CH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1)[CH:70]=[CH2:71]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:14]([C:15](=[O:16])[N:72]([CH2:69][CH:70]=[CH2:71])[CH:73]2[CH2:77][CH2:76][CH2:75][CH2:74]2)[CH:13]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: C=CCNC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a strrred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-allylcyclopentylamine (0.029 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.030 g) obtained by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:35]=[CH:34][C:10]([CH2:11][CH:12]([NH:24][S:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:13]3[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[N:3]1.[C:36](OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(S(C2C=CC=CN=2)(=O)=O)NCC2C=CC(C3SC=CN=3)=CC=2)N=1)(C)(C)[CH3:37]>>[CH2:36]([O:22][C:21](=[O:23])[CH2:20][NH:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[CH:5][CH:4]=[N:3]3)=[CH:35][CH:34]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:18]=1)[CH3:37]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Reactant: O=C(O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: Cl
Product: CCOC(=O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 95 %

Procedure:
Reaction was carried out in the same manner as in Example 27 except for using (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride (21.6 mg, 0.0367 mmol) obtained in Example 7-(b) in place of tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (17.6 mg) as a colorless oil. (Yield: 95%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of 1-(4-bromophenyl)ethanone (10.0 g, 50.25 mmol, 1.00 equiv) in acetic acid (50 mL). This was followed by the addition of a solution of bromine (8.2 g, 1.05 equiv) in acetic acid (50 mL) dropwise with stirring at 60° C. over 90 min. The resulting solution was stirred for 3 h at 60° C. The resulting mixture was concentrated under vacuum. The crude product was re-crystallized from petroleum ether/ethyl acetate in the ratio of 7:1. This resulted in 9.3 g (67%) of the title compound as a yellow solid.
Reaction SMILES: C(OCC)(=O)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[C:24]3C(=O)OC(C)(C)[O:26][C:25]3=[O:33])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.[BH4-].[Na+]>CCO>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:33])=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(COc2ccc(C=C3C(=O)OC(C)(C)OC3=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring ethyl acetate (100 mL) solution of 5-[[4-[(4-methoxyphenyl)methoxy]phenyl]-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (200 mg, 0.543 mmol) was added EtOH (4 mL), followed by NaBH4 (62 mg, 1.63 mmol). The reaction mixture was stirred at room temperature for 15 minutes, quenched with water (5 mL), extracted with EtOAc (10 mL). The extract was washed with brine, dried over MgSO4, filtered, and concentrated to a white solid. A solution of this white solid in 3:1 pyridine-water (5 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled to room temperature and put in an ice-water bath. Concentrated HCl was carefully added to pH ˜2. The resulting suspension was extracted with ethyl acetate (10 mL×3), dried over MgSO4, filtered, and concentrated to an off-white solid. Preparative HPLC gave compound 37 as a white solid. MS ESI (neg.) m/e: 285.0 (M−1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[NH:15][C:16]([C:26](F)(F)F)=[N:17][C:18]=3[C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:8]=2[N:7]([CH3:30])[C:6]1=[O:31])[CH:2]([CH3:4])[CH3:3].[OH-].[NH4+:33]>>[CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[NH:15][C:16]([C:26]#[N:33])=[N:17][C:18]=3[C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:8]=2[N:7]([CH3:30])[C:6]1=[O:31])[CH:2]([CH3:4])[CH3:3]
Reactant: [NH4+]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc3c(c2)n(C)c(=O)n3CC(C)C)c1
Agent: [OH-]
Product: Cc1cccc(-c2nc(C#N)[nH]c2-c2ccc3c(c2)n(C)c(=O)n3CC(C)C)c1
Reaction time: 120 h

Procedure:
1-Isobutyl-3-methyl-5-(5-m-tolyl-2-trifluoromethyl-3H-imidazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (prepared as described previously using the method described for example 63 and Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17(11), 1182–1188, 20 mg, 0.05 mmol) was suspended in 5% aqueous ammonium hydroxide solution (4.7 mL). The suspension was stirred for 5 days, after which time the reaction was concentrated in vacuo. The resulting material was purified by LC (Waters Symmetry C8, acetonitrile/water 40% to 100%) to afford 8 mg of the title compound as a white solid. MS (M+1)=386.2
Reaction SMILES: [NH2:1][C:2]12[CH2:10][N:9](C(OC)=O)[CH2:8][CH:7]1[CH:6]=[CH:5][CH:4]=[CH:3]2>O>[CH2:8]1[CH:7]2[C:2]([NH2:1])([CH:3]=[CH:4][CH:5]=[CH:6]2)[CH2:10][NH:9]1
Reactant: COC(=O)N1CC2C=CC=CC2(N)C1
Solvent: O
Product: NC12C=CC=CC1CNC2

Procedure:
Analogously to Step F, 1.4 g (7.2 mmol) of methyl 1-amino-8-azabicyclo[4.3.0]nona-2,4-diene-8-carboxylate are hydrolysed using 4 g of Ba(OH)2.8H2O in 20 ml of water and worked up accordingly. Yield: 0.6 g (61% of theory), boiling point: 65° C./0.1 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14].CC(C)=O.C(=O)=O>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:13](=[O:14])[C:12]([F:19])([F:18])[F:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C=O
Agent: [Mg]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1)C(F)(F)F
Temperature: -10 °C
Yield: 47.4 %

Procedure:
A solution of p-chlorobenzyl chloride (80.5 g, 0.5 mol) and ether (150 mL) is slowly added to a vigorously stirred slurry of magnesium turnings (12.15 g, 0.5 mol) and ether (50 mL) over a 45 minute period. After the addition is complete, the reaction mixture is refluxed for 1/2 hour then cooled in an ice bath. The Grignard reagent is then added to a solution of ethyl trifluoroacetate (71.04 g, 0.5 mol) and ether (150 mL) at -60° to -70° C. (acetone-dry ice bath) over a 45 minute period. The cooling bath is removed and the reaction mixture is allowed to warm to -10° C. The reaction mixture is then quenched with saturated ammonium chloride solution and then acidified with 10% hydrochloric acid solution. The organic layer is separated, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a liquid. Vacuum distillation of the liquid gives the title product as a clear liquid (52.8 g, bp 72°-74° C./34 mm, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:13][N:12]=[CH:11][N:10]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: COc1ccc(CNc2ncns2)cc1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
To a solution of N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (1.40 g, 6.33 mmol) in THF (42.2 mL) at −70° C. under an argon atmosphere was added lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (6.96 mL, 6.96 mmol) dropwise. The reaction mixture was removed from cooling and stirred for 45 min. The mixture was again cooled to −70° C. (internal temperature) to give a yellow suspension. Then solid 1-chloroisoquinoline-6-sulfonyl chloride (1.82 g, 6.96 mmol) was added in one portion. After 15 min, the mixture was warmed to room temperature and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide 1-chloro-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (0.73 g, 1.633 mmol) as an orange solid. MS (ESI): 447.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 3.65 (s, 3H), 5.24 (s, 2H), 6.77 (m, J=8.66 Hz, 2H), 7.28 (m, J=8.66 Hz, 2H), 8.10 (dd, J=5.9, 10.8 Hz, 1H), 8.15 (d, J=6.4 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.45 (s, 1H), 8.50 (d, J=5.56 Hz, 1H), 8.77 (d, J=1.71 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([NH:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH:7]=1
Reactant: [NH-]S(=O)(=O)c1ccc(F)cc1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(F)cc2)n1
Yield: 55.9 %

Procedure:
0.46 g (0.0026 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 1.1 g (0.0051 mol) of 4-fluoro-benzenesulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone in 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was saturated with sodium chloride, evaporated briefly in a vacuum and made acid with 4N HCl, with a precipitate separating. The mixture was suctioned filtered, the extract and the solid were combined and chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. The product was recrystallized from ethyl acetate/n-hexane. There was obtained 0.46 g (56%) of N-(6-chloro-2-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide as white crystals; m.p. 121-123° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:51][CH2:52][O:53][CH2:54][CH2:55]Br.C(O)(C(F)(F)F)=O>ClCCCl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([N:1]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH2:3][CH2:4]3)[CH:10]=2)[CH2:39][CH2:40]1
Reactant: BrCCOCCBr
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](N4CCOCC4)CC3)nn12
Temperature: 60 °C
Reaction time: 9 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.184 mmol) in 1,2-dichloroethane (2 mL) was added DIEA (0.128 mL, 0.734 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (42.6 mg, 0.184 mmol), and the reaction solution was stirred at 60° C. for 9 hrs. The reaction mixture was treated with TFA (0.849 mL, 11.02 mmol) at 65° C. for 1 hr, concentrated, diluted with methanol, and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to obtain 8-(cyclopropylamino)-N-(2-fluoropyridin-4-yl)-6-((trans)-4-morpholinocyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (36.3 mg, 0.073 mmol, 40.0% yield). LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.67 minutes. [M+H]=495.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (1H, s), 9.57-9.89 (1H, m), 8.26 (1H, d, J=5.77 Hz), 7.99 (1H, d, J=1.76 Hz), 7.67 (1H, s), 7.60 (1H, s), 7.44 (1H, d, J=4.77 Hz), 6.88-7.14 (1H, m), 5.98 (1H, s), 4.04 (2H, d, J=11.80 Hz), 3.58-3.83 (3H, m), 3.40 (2H, d, J=12.05 Hz), 2.98-3.23 (2H, m), 2.28 (2H, d, J=11.80 Hz), 2.17 (2H, d, J=11.29 Hz), 1.55 (2H, br. s.), 1.35 (2H, br. s.), 0.78 (2H, d, J=6.53 Hz), 0.63 (2H, br. s.)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cccc(NO)c1
Product: O=[N+]([O-])c1ccc(C=[N+]([O-])c2cccc(CO)c2)cc1
Yield: 81 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 4-nitrobenzaldehyde (58) (1.51 g, 10 mmol) afforded, after workup, a red solid. The crude product was recrystallized from acetone/petroleum ether to obtain 2.21 g (8.1 mmol, 81%) of 93 as a red crystalline solid: mp 207°-209° C.; IR (Nujol) 3260, 1590, 1555, 1510, 1320, 1150, 1020, 860 cm-1 ; 1H NMR (Me2SO-d6) δ 4.60 (d, J=5.6 Hz, 2H), 5.43 (t, J=5.7 Hz, 1H), 7.49-8.71 (m, 9H); 13C NMR (Me2SO-d6) δ 62.85, 119.99, 120.38, 124.29, 128.83, 129.47, 129.96, 132.70, 137.36, 144.79, 147.83, 148.94. Anal. Calcd for C14H12N2O4 : C, 61.76; H, 4.41. Found: C, 62.09; H, 4.59.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][NH:8][CH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([O:23]C)[C:14]([O:21]C)=[N:15]2)(C)(C)C>Br.C(O)(=O)C.C(OCC)C>[BrH:20].[Br:20][C:18]1[CH:17]=[C:16]2[C:11]([NH:12][C:13](=[O:23])[C:14](=[O:21])[NH:15]2)=[C:10]([CH2:9][NH:8][CH2:7][C:6]([OH:25])=[O:5])[CH:19]=1
Reactant: COc1nc2cc(Br)cc(CNCC(=O)OC(C)(C)C)c2nc1OC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CNCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
380 mg (0.921 mmol) of N-(7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-glycine tert-butyl ester are dissolved in 6 ml of an approximately 25% solution of hydrogen bromide in acetic acid and the solution is stirred for two hours at 70° C. The mixture is cooled to 20° C. and diluted with diethyl ether. The solid is filtered off and washed with diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[CH2:5][CH2:4][CH:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CO.[BH4-].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH:6]([OH:10])[CH2:5][CH2:4][CH:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1CCC(=O)C(CC)C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(O)C(CC)C1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 22.5 g. of ethyl 2-methyl-3-ethyl-4-ketocyclohexanecarboxylate (all-cis form, m.p. 28°-32°) in 450 ml. of methanol is stirred and maintained at a temperature of 5°-7° C. while a total of 11.0 g. of sodium borohydride is added over a period of 40 minutes. The reaction mixture is stirred at 5° C. for an additional one hour after which a total of 40 ml. of acetic acid is added cautiously to neutralize the base. The methanol solution if evaporated under vacuum to a pasty residue which is shaken with ether and water. The ether phase is washed with aqueous sodium bicarbonate and is dried and evaporated to yield a colorless oil. Upon distillation of the oil, 21.5 g. of ethyl 2-methyl-3-ethyl-4-hydroxycyclohexanecarboxylate is obtained as a mobile oil having a boiling point of 88°-91° at 0.001 mm.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([S:14]C(=O)C)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].Cl>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([SH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)SC1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(S)C1
Yield: 101.4 %

Procedure:
200 g of N-BOC-3(R,S)-acetylthio-piperidine are placed in a 10 l reactor with 3.4 l of methanol in an inert atmosphere. To this solution 42 g of sodium methoxide in methanol is added over a period of 15 min. After additional stirring 170 ml of 5 n HCl are added, bringing the pH-value to 2.6-3. The solution is concentrated at an evaporator. The resulting biphasic mixture is taken up with 1.7 l of methyl tert.-butyl ether (MTBE) and 1.7 l of water. After shaking, separation of the aqueous phase and washing the MTBE phase is isolated and evaporated, yielding 170 g of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:25][CH:26]=[CH2:27])[CH2:9][CH:8]([O:10][Si](C(C)(C)C)(C)C)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@:5]1([CH2:25][CH:26]=[CH2:27])[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:4]
Reactant: C=CCC1(C(=O)OC)CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(C(=O)OC)C[C@@H](O)CN1C(=O)OC(C)(C)C

Procedure:
3.3 g (8.27 mmol) (2R,4R)-(2-allyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester are dissolved in 60 mL THF, cooled below 5° C. and treated with 8.68 mL (1.05 eq) 1 M TBAF in THF under stirring. The reaction mixture is allowed to slowly reach room temperature, while being stirred another 4 h. Ice and AcOEt are added, the mixture washed with brine twice, and the organic phase evaporated to yield a crude product which is column chromatographed (silica gel, TBME/petroleum ether 1:1) to yield 1.8 g desired product as a colorless, thick oil, which is used as such in the next step.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12]([C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH3:25])=O>C1(C)C=CC=CC=1.C1COCC1>[CH3:25][C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[CH2:12][OH:11]
Reactant: COC(=O)c1oc(-c2ccccc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccccc2)oc1CO
Temperature: -78 °C
Reaction time: 8 h

Procedure:
19.0 mL of 1.0 M DIBAL-H solution in toluene is added slowly to a solution of 1.63 g (7.5 mmol) of 4-methyl-2-phenyl-oxazole-5-carboxylic acid methyl ester (J. Chem. Soc., Chem. Comm. 1995, 22, 2335) in 30 mL of THF at −78° C. The cooling bath is removed, and the reaction mixture is stirred overnight. The reaction mixture is cooled to −78° C. and quenched with 9 mL of MeOH. The cooling bath is removed, and 9 mL of brine and 6.5 g of Na2SO4 are added, and the reaction mixture is stirred vigorously for 2 h, and then filtered off, and concentrated in vacuo to produce (4-methyl-2-phenyl-oxazol-5-yl)-methanol as a solid; 1H NMR (250 MHz, CDCl3) δ7.93-8.01 (m, 2H), 7.37-7.43 (m, 3H), 4.65 (s, 2H), 2.61 (br, s, 1H), 2.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[F:31][CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:34][CH2:33][CH2:32][F:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCCF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCF)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-fluoroethylamine hydrochloride (20 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(2-fluoroethyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[C:21]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH3:37])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH2:37][Br:8])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(CBr)nc2ccccc21
Reaction time: 21 h

Procedure:
NBS (8.43 g, 47.4 mmol) and AIBN (2.1 g, 12.8 mmol) were added to a solution of 1-BOC-2-methylbenzimidazole (10.0 g, 43.1 mmol) in CCl4 (120 mL) at reflux. After 21 h, the reaction was cooled and filtered. The filtrate was concentrated, and the resulting brown oil was chromatographed (silica gel, 15% EtOAc/hexanes) to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 7.94-8.01 (m, 1 H), 7.70-7.75 (m, 1 H), 7.31-7.44 (m, 2 H), 4.96 (s, 2 H), 1.75 (s, 9 H),