Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.C1COCC1.N1CCNCC1>C(N(CC)CC)C>[CH3:19][CH:20]1[NH:21][CH:22]([CH3:26])[CH2:23][N:24]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:25]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CC(C)NC(C)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 2,6-cis-dimethylpiperazine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperazine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to a colorless solid (79 mg, 85%). 1H NMR (CDCl3) 1.03 (d, J=4.8, 6 H), 1.72-2.20 (m, 1 H), 2.29 (s, 3 H), 2.58 (br, 1 H), 2.78-2.90 (m, 2 H), 4.25 (br, 2 H), 7.24-7.26 (m, 1 H), 7.37-7.39 (m, 1 H). 13C NMR 7.9, 19.4, ˜50 (br obsc), 51.3, 114.7, 118.7 (q, J=271), 128.0, 129.3, 131.2, 140.2, 155.1 (q, J=40), 157.9, 162.4. 19F NMR −63.2. LC/MS 4.43 min, [M+1]+374.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][CH2:40][OH:41])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[C:43]1[C:44]([I:53])=[N:45][CH:46]=[C:47]([CH:52]=1)[C:48]([O:50][CH3:51])=[O:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[I:53][C:44]1[C:43]([O:41][CH2:40][CH2:39][C:35]2[N:34]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:38]=[CH:37][N:36]=2)=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][N:45]=1
Reactant: OCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cnc(I)c(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cnc(I)c(OCCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 3 h
Yield: 43.6 %

Procedure:
Diisopropyl azodicarboxylate (1160 uL, 5.90 mmol) was added dropwise to a mixture of 2-(1-trityl-1H-imidazol-2-yl)ethanol (1900 mg, 5.4 mmol), methyl 5-hydroxy-6-iodonicotinate (1570 mg, 5.63 mmol) and Triphenylphosphine (1550 mg, 5.90 mmol) in Tetrahydrofuran (45.0 mL, 555 mmol) at 0° C. After stirring for 3 hours the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuum. The residue was purified on 40 g silica column eluting with 50% ethyl acetate in DCM to give 1.45 g (44%) of methyl 6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate. MS (ESI+): 616.0. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=1.9, 1H), 7.40-7.28 (m, 10H), 7.20-7.16 (m, 6H), 6.99 (d, J=1.5, 1H), 6.81 (d, J=1.5, 1H), 3.98-3.91 (m, 5H), 2.46 (t, J=7.3, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[C:16]2[C:8]([CH2:9][CH2:10][C:11]3([O:15]2)[CH2:14][CH2:13][CH2:12]3)=[CH:7][C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].[CH2:19]=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>O1CCOCC1>[C:1]([C:5]1[CH:17]=[C:16]2[C:8]([CH2:9][CH2:10][C:11]3([O:15]2)[CH2:14][CH2:13][CH2:12]3)=[C:7]([CH2:19][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:6]=1[OH:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: C1COCCN1
Reactant: CC(C)(C)c1cc2c(cc1O)CCC1(CCC1)O2
Solvent: C1COCCO1
Product: CC(C)(C)c1cc2c(c(CN3CCOCC3)c1O)CCC1(CCC1)O2
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 7-tert-butylspiro[chroman-2,1′-cyclobutan]-6-ol (2.8 g) in dioxane (5 mL) was added an aqueous formaldehyde solution (3.7 mL, 37% in H2O) followed by morpholine (4.0 mL). The reaction was stirred under argon at 90° C. for 2.5 hours, cooled in an ice bath with stirring to precipitate product which was filtered off as a white solid, washed with H20, and air dried to give 7-tert-butyl-5-(morpholinomethyl)spiro[chroman-2,1′-cyclobutan]-6-ol (2.45 g). 1H-NMR (300 MHz, CDCl3) δ=10.74 (s, 1H), 6.73 (s, 1H), 3.77 (br s, 4H), 3.68 (s, 2H), 2.67-2.63 (t, 2H), 2.59 (br s, 4H), 2.29-2.24 (m, 2H), 2.08-1.94 (m, 5H), 1.70-1.65 (m, 1H), 1.40 (s, 9H) ppm. 13C-NMR (75 MHz, CDCl3) δ=150.32, 145.73, 136.19, 118.32, 117.55, 115.00, 76.22, 66.81, 56.78, 52.69, 34.60, 33.91, 29.53, 20.01, 12.46 ppm. MS (m/z)=346 (M+H+), 259 [M-morpholine+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.[C:15]1(B(O)O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>O.C(O)C.C1C=CC=CC=1.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>[C:23]1([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=2)[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Nc1ccc(Br)cn1
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: [K+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cccc3ccccc23)cn1

Procedure:
Potassium carbonate (5.19 mmol, 717 mg) in water (2.5 mL) and tetrakis(triphenylphosphine)palladium(0) (0.04 mol %, 80 mg) in ethyl alcohol (2.5 mL) were added to 2-amino-5-bromopyridine (1.73 mmol, 299 mg) and 1-naphthaleneboronic acid (2.60 mmol, 446 mg) in benzene (10.0 mL). After 2 hours at 90° C. the reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3×30 mL). The organic phases were concentrated in vacuo and the residue chromatographed on silica gel (eluted with 50% ethyl acetate in hexanes) to give 260 mg (Y: 68%) of the title compound 11a. MS (E+) m/z: 381 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:25][C:26](=O)[O:27]C1C=CC=CC=1.[CH2:35]([NH2:37])[CH3:36]>CS(C)=O>[CH3:22][O:21][C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:23][CH3:24])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:25][C:26]([NH:37][CH2:35][CH3:36])=[O:27])=[C:2]([F:1])[CH:7]=1)=[O:20]
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)ccnc2cc1OC
Reactant: CCN
Solvent: CS(C)=O
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)OC)cc23)cc1F

Procedure:
Phenyl N-(2-fluoro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate (0.9 g) was treated with ethylamine in dimethylsulfoxide at room temperature in the same manner as Example 11, to obtain the title compound (0.6 g) as a solid.
Reaction SMILES: [CH2:1]([CH:4]1[N:8]([CH3:9])[S:7](=[O:11])(=[O:10])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3].[C:13]1([S:19][CH2:20]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:13]1([S:19][CH2:20][N:6]2[C:5](=[O:12])[CH:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH3:9])[S:7]2(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCSc1ccccc1
Reactant: CCCC1C(=O)NS(=O)(=O)N1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Yield: 57.7 %

Procedure:
A mixture of 4-propyl-5-methyl-1, 2,5-thiadiazolidin-3-one 1,1-dioxide (9 g) , phenylthiomethyl chloride (7.43 g) and tetrabutylammonium bromide (1 g) was suspended in 200 ml of toluene, refluxed for 8 hours, cooled, and concentrated in vacuo. The residue was purified by flash chromatography (15-20% ethyl acetate in hexane) to afford 8.5 g (88%) of 2-phenylthiomethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =CH3) as an oil.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:20][C:21]([NH:23][C@H:24]([C:40]([NH:42][C@H:43]([C:47]([OH:49])=[O:48])[C@@H:44]([CH3:46])[OH:45])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29]C(OCC1C=CC=CC=1)=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O1CCCC1.[Pd]>[C:1]([O:18][CH:19]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:20][C:21]([NH:23][C@H:24]([C:40]([NH:42][C@H:43]([C:47]([OH:49])=[O:48])[C@@H:44]([CH3:46])[OH:45])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 63.6 %

Procedure:
N-[Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysyl]-L-threonine (2.4 g) prepared by the method of Example 40 was dissolved in tetrahydrofuran (30 ml), and palladium black (0.3 g) added thereto. The mixture was subjected to catalytic hydrogenation at atmospheric pressure. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel. Elution with a mixture of chloroform and methanol (50:1) afford powder of N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-lysyl]-L-threonine (1.3 g).
Reaction SMILES: N(OCCCC)=O.[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39](N)=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.II.[I:49]CI>C1COCC1.[Cu]I>[C:8]([O:16][CH:17]1[CH:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][CH:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39]([I:49])=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: ICI
Agent: [Cu]I
Agent: CCCCON=O
Agent: II
Solvent: C1CCOC1
Product: CCNC(=O)C1OC(n2cnc3c(Cl)nc(I)nc32)C(OC(=O)c2ccccc2)C1OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
n-Butyl nitrite (4.65 ml, 39.7 mmol) was added to a suspension of (2R,3R,4S,5S)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 46) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7 mmol), copper(1) iodide (6.16 g, 32.3 mmol) and diiodomethane (12.55 ml, 155.8 mmol) in THF (100 ml) and the mixture was heated under reflux for 2.5 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between aqueous sodium metabisulfite solution (5% w/v, 100 ml) and dichloromethane (100 ml). The organic layer was separated, filtered through Arbocel (trade mark), dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) to afford the title compound as a yellow foam (7.55 g, 78%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C@H:3]([OH:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:5][C:4](=[O:6])[C@@H:3]([OH:7])[C:2]([CH3:9])([CH3:8])[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](O)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
(S)-3,3-dimethyl-2-hydroxybutyric acid (2.1 grams, 15.9 mmol) and triethylamine (3.3 mL, 23.8 mmol) were dissolved in 15 mL DMF. Benzyl bromide (2.8 mL, 23.8 mmol) was added and the mixture was stirred overnight. Ethyl acetate was added and the mixture was washed with water (3×) and sat'd NaCl then dried over sodium sulfate and concentrated. Flash chromatography (150 g silica, 7/1 Hexane/EtOAc) afforded 3.4 grams (96%) of the title compound. 1H NMR (300 MHz, CDCl3). δ 0.98 (s, 9H), 2.75 (d, 1H), 3.85 (d, 1H), 5.23, (s, 21), 7.27-7.3 (m, 5H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C>C([O-])(O)=O.[Na+].CCOCC>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC#CCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(tert-butyldimethylsilyoxymethyl)-4-(2-decynyl)benzene (51) (313 mg, 0.87 mmol) in CH:CN (10 mL) was added 50% aqueous HF (1 mL), the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured in saturated NaHCO3 (50 mL) and ether (75 mL). The organic layer was separated and washed with two 50-mL portions of water, dried (MgSO4) and concentrated to yield the alcohol derivative. The latter was dissolved in EtOAc (10 mL) and 5% Pd/C was added. Hydrogen was then bubbled through the reaction mixture for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield 4-decylphenylmethanol (52) is a clear oil; 1H NMR (CDCl3) δ7.28 (d, J=7.8 Hz, 2 H), 7.18 (d, J=8.1 Hz, 2 H), 4.65 (s, 2 H), 2.61 (t, J=7.8 Hz, 2 H), 1.83 (s, 1 H), 1.61 (m, 2 H), 1.25 (m, 16 H), 0.90 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 142.68, 138.25, 128.76, 127.27, 65.41, 35.80, 32.04, 31.69, 29.65, 29.75, 29.46, 26.06, 22.83, 14.27. ##STR26##
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH2:23][CH2:22]1>>[ClH:1].[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[N:4][N:3]=[C:2]2[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[CH2:25][CH2:26]2)=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: COc1cc(-c2ccccc2)c2cnnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1cc(-c2ccccc2)c2cnnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Product: Cl

Procedure:
This compound is obtained according to the procedure described in 2.4. by reacting 1-chloro-7-methoxy-5-phenylphthalazine with 4-amino-1-(naphthalen-2-yl-methyl)piperidine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][C@H:4]1[O:17][CH3:18].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH2:5][C@H:4]1[O:17][CH3:18])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1CO
Solvent: ClCCl
Product: CO[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of tert-butyl [(1S,3R,4R)-4-(hydroxymethyl)-3-methoxycyclohexyl]carbamate (racemic) (671 mg, 2.59 mmol) in dichloromethane (8 mL) was added methanesulfonyl chloride (0.401 mL, 5.18 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then concentrated and partitioned between ethyl acetate and water. The organic phase was concentrated and purified by flash chromatography (eluting with a gradient of 50% ethyl acetate in hexanes) to give the desired product (0.87 g, 100%). LCMS calculated for C9H16NO5S (M+H-t-Bu-MeOH)+: m/z=250.1. Found: 250.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([CH2:11][CH2:12]OS(C)(=O)=O)[C:7]1=[O:26].[CH2:31]([O:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH3:32]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C:8]([CH2:11][CH2:12][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:37]3[N:36]([CH2:35][CH2:34][O:33][CH2:31][CH3:32])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:51][CH2:50]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]1=[O:26]
Reactant: COc1ccccc1CN1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN(Cc4ccccc4OC)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 18.5 using 1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.76 g, 2.65 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (1.15 g, 2.65 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give the title compound: Rf=0.38 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.Cl.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[N:10]=[CH:11][C:3]=12
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C)cnc(Cn2ncc3c(Cl)nc(N)nc32)c1C
Temperature: 80 °C
Yield: 17.2 %

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (1.76 g), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride (3.70 g), K2CO3 (5.17 g), and DMF (20 ml) was heated to 80° C. for 30 min, diluted with EtOAc, washed with water and brine, concentrated, and purified by flash chromatography to give the title compound as a white solid (0.57 g). R.t. 4.46 min. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 7.89 (s, 1H), 5.53 (2H), 5.24 (br. s, 2H), 3.74 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:40])[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(Cl)Cl>[OH:11][N:12]([CH:13]([CH2:14][S:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:29]=2)[CH2:22][CH2:23]1)(=[O:16])=[O:17])[CH2:38][C@@H:39]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:40])[CH:1]=[O:3]
Reactant: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccc3)cc2)CC1)NO)c1ccccc1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccc3)cc2)CC1)N(O)C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
To formic acid (2.5 mL, 65 mmol) at 0° C. was added acetic anhydride (500 μL, 5.2 mmol) and the mixture was stirred at 0° C. for 10 minutes. This was added to a solution of 1-{[(4S)-2-(hydroxyamino)-4-phenylpentyl]sulfonyl}-4-[4-(phenylethynyl)phenyl]piperazine (345 mg, 0.685 mmol) in CH2Cl2 (5 mL) cooled to 0° C. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo. The residue was then precipitated in MeOH (10 mL) and heated to 40° C. for two hours, dissolving. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 1–2% MeOH in CH2Cl2) to give the title compound as a white foam (330 mg, 0.621 mmol, 91%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[C:7]([CH3:21])[O:6][N:5]=1>CO>[CH3:3][C:4]1[C:8]([CH2:9][N:10]2[CH:18]([OH:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[C:7]([CH3:21])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1CN1C(=O)c2ccccc2C1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaBH4 (36 mg, 0.938 mmol) was added slowly to a stirring mixture of 2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-isoindole-1,3-dione (20 mg, 0.781 mmol) in methanol (2 mL). After stirring at room temperature for 10 minutes, the reaction was quenched with acetic acid (1 mL) and partitioned between water and dichloromethane. The organic layer was washed several times with water and concentrated under vacuum to give the sub-title compound as a white solid. MS: ESI (positive): 259 (M+H).
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]([C:55]#[N:56])[CH:51]=[C:52]([F:54])[CH:53]=1.[CH2:57]([O:59]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:58]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:57]([C:48]1[CH:49]=[C:50]([C:55]#[N:56])[CH:51]=[C:52]([F:54])[CH:53]=1)(=[O:59])[CH3:58]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(F)cc(C#N)c1

Procedure:
824 mg (0.900 mmol) of tris(dibenzylideneacetone)dipalladium and 1.23 g (1.98 mmol) of rac-1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) are added to 9.00 g (45.0 mmol) of 3-bromo-5-fluorobenzenecarbonitrile in toluene (300 ml) under an argon atmosphere. After the addition of 19.5 g (54.0 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 300 ml of THF. After the addition of 100 ml of an aqueous 2N hydrogen chloride solution the mixture is stirred at room temperature for 2 h. The reaction mixture is subsequently neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9:1). 7.11 g (97% of theory) of the title compound are obtained.