Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[OH:2][C@@H:3]([C@H:5]1[C:25](=[O:26])[N:7]2[CH:8]([C:12]([O:14]CC3C=CC([N+]([O-])=O)=CC=3)=[O:13])[C:9](=O)[CH2:10][C@H:6]12)[CH3:4].[CH3:27][N:28]([CH3:39])[C:29]([C@@H:31]1[CH2:35][C@H:34]([SH:36])[CH2:33][N+:32]1([CH3:38])[CH3:37])=[O:30]>C(#N)C.C(N(C(C)C)CC)(C)C.O1CCCC1.P([O-])([O-])([O-])=O.[Pd]>[CH3:38][N+:32]1([CH3:37])[CH2:33][C@@H:34]([S:36][C:9]2[CH2:10][C@@H:6]3[C@@H:5]([C@H:3]([OH:2])[CH3:4])[C:25](=[O:26])[N:7]3[C:8]=2[C:12]([O-:14])=[O:13])[CH2:35][C@H:31]1[C:29](=[O:30])[N:28]([CH3:27])[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)C[N+]1(C)C
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(=O)N(C)C)[N+](C)(C)C3)C[C@H]12
Reaction time: 1 h
Yield: 22.5 %

Procedure:
126 μl of diisopropylethylamine and 132 μl of diphenylphophoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 218 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate dissolved in 3 ml of dry acetonitrile, and the mixture was stirred at the same temperature for 1 hour. At the end of this time, a solution of 243 mg of the crude (2S, 4S)-2-(N,N-dimethylcarbamoyl)-1,1-dimethyl-4-mercaptopyrrolidinium salt [prepared as described in Example 4-(1)] in 2 ml of dry acetonitrile and 144 μl of diisopropylethylamine were added to the mixture, whilst ice-cooling. The mixture was then allowed to stand at the same temperature for 5 hours and then for 2 days in a refrigerator. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 6. The crude product was dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2 hours in the presence of 200 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified in a similar manner to that described in Example 6, to afford 56 mg of the title compound.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:28]([CH3:27])(=[O:30])=[O:29])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes methanesulfonylchloride (0.11 ml, 158 mg, 1.38 mmol). The mixture was stirred for 48 h, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with 90:10:1 ethyl acetate:methanol:ammonia solution (0.880), then in 80:20:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (212 mg, 82%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40](O)=[O:41])[CH:36]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:40]([C:37]5[CH:36]=[C:35]([CH3:34])[O:39][N:38]=5)=[O:41])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C(=O)O)no1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)no1
Yield: 22.3 %

Procedure:
{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-(5-methyl-isoxazol-3-yl)-methanone (14 mg, 22%) was prepared as a white solid using the conditions described in Example 152, by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27, 63 mg, 0.13 mmol) with 5-methylisoxazole-3-carboxylic acid (available from Alfa Aesar, Ward Hill, Mass., USA; 20 mg, 0.16 mmol) in the presence of TSTU (O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 78 mg, 0.26 mmol) and diisopropylethylamine (0.14 mL, 0.8 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]S([O-])(=O)=O)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.[C-]#[N:37].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:37])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCCS(=O)(=O)[O-])c23)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCC#N)c23)cc1

Procedure:
Stir a mixture of 400 mg (approx. 0.80 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidin-4-yl]amino}hexyl-methanesulphonate and 526 mg (8.1 mmol) potassium cyanide in 20 ml DMF overnight at 80° C. After cooling, dilute with ethyl acetate and wash with water and saturated sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). 249 mg (72% of theor.) of the title compound is obtained as a yellowish oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[ClH:21]>CN(C)C=O.CCOCC>[ClH:21].[CH2:9]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Oc1ccc(SC2CCCc3cccnc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCOc1ccc(SC2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.72 g (24 mmol) of sodium hydride were added to a solution of 5.15 g (20 mmol) of 8-(4-hydroxyphenylthio)-5,6,7,8-tetrahydroquinoline in 26 ml of dimethylformamide under nitrogen. When effervescence had ceased, 3.29 g (24 mmol) of n-bromobutane were added dropwise with ice-cooling. After stirring at room temperature overnight, the mixture was poured into ice-cold water and extracted with ether to obtain a brown oil. A solution of the oil in ether was treated with ethereal hydrogen chloride to precipitate 4.89 g (70%) of 8-(4-n-butoxyphhenylthio)-5,6,7,8-tetrahydroquinoline hydrochloride as pale yellow crystals (from ethanol-ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:17])([CH2:15]O)[CH2:13]O>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:17])[CH2:15][O:10][B:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:9][CH2:13]1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(CO)CO
Solvent: Cc1ccccc1
Product: CC1(C)COB(c2ccc(O)cc2)OC1
Yield: 96.4 %

Procedure:
A solution of 4-hydroxyphenyl boronic acid (15.0 g) and 2,2-dimethyl-1,3-propanediol (11.4 g) in toluene (100 mL) was heated under reflux for 6 hours 30 minutes (using Dean-Stark apparatus). The resultant reaction mixture was allowed to cool and stand still and therefrom, a precipitates were filtered out and the solvent was distilled off under reduced pressure to obtain the subject compound (21.6 g) as a light gray solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:46][N:47]([CH3:49])[NH2:48].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([NH:48][N:47]([CH3:49])[CH3:46])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a solution of 4-benzylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester (0.75 g, 2.35 mmol) (prepared as in Gilligan et al J. Med. Chem. 1994, 364-370) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.32 mg, 2.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol) and the mixture was stirred for 30 min. Then N′,N′-dimethylhydrazine (0.27 ml, 3.53 mmol) and diisopropylethylamine (0.52 ml, 3.06 mmol) was added and the mixture was stirred for 2 days. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with heptane/ethyl acetate (1:2) to give 0.76 g of 4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C=Nc1ccccc1
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Yield: 58 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem., 1983, 26, p. 1582 and J. Med. Chem., 1986, 29, p. 2194) (1.0 g, 4.6 mmol) in ethanol (4 ml) under argon was treated with phenylisocyanate (0.55 g, 4.6 mmol) and the reaction was heated at reflux temperature for 4 hours. The product precipitate out of the reaction. The reaction was then concentrated in vacuo and the residue was triturated with isopropylether to give the title compound as a colorless solid (0.9 g, 63%), m.p. 240-241° C.: 1H NMR (CDCl3 /DMSO) δ 8.3 (s, 1 H), 7.7 (s, 1 H), 7.4 (d, J=8.0 Hz, 3 H), 7.26 (t, J=8.0 Hz, 2 H), 7.0 (t, J=9.0 & 7.0 Hz, 1 H), 6.86 (d, J=9.0 Hz, 1 H), 6.4 (d, J=8.0 Hz, 1 H), 5.3 (d, J=5.0 Hz, 1 H), 4.9 (t, J=9.0 & 8.0 Hz, 1 H), 3.6 (dd, J=4.0 & 6.0 Hz, 1 H), 1.5 (s, 3 H), 1.3 (s, 3 H); 13C NMR (CDCl3 /DMSO) 157.0, 156.5, 139.1, 132.2, 132.1, 128.4, 123.9, 121.8, 118.2, 117.8, 80.0, 74.3, 49.9, 26.1, 18.4; IR (KBr) 1132, 1267, 1491, 1550, 1612, 1645, 2226, 2932, 2978, 3433 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br-].[C:33]1([P:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1C=CC=CC=1>[Br-:19].[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][P+:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Br-]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reaction time: 24 h
Yield: 34 %

Procedure:
Bromination of 2-chloro-4-nitrotoluene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 24 h and the displacement reaction was performed at 20° C. for 7 d, gave the crude phosphonium salt (559) (34%) as a light brown solid, mp (benzene) 70–75° C. (dec). 1H NMR [(CD3)2SO] δ 8.21 (d, J=2.5 Hz, 1H), 8.13 (dd, J=8.7, 2.5 Hz, 1H), 7.94 (td, J=7.5, 1.6 Hz, 3H), 7.80–7.66 (m, 12H), 7.43 (dd, J=8.5, 2.6 Hz, 1H), 5.33 (d, J=15.7 Hz, 2H). FABMS found M+=432.0916, 434.0904. C25H20ClNO2P requires 432.0921, 434.0891.
Reaction SMILES: [CH3:1][S:2]([O:5]C)(=[O:4])=[O:3].[CH3:7][N+:8]1[CH:12]=[CH:11][NH:10][CH:9]=1>>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:7][N+:8]1[CH:12]=[CH:11][N:10]([CH3:1])[CH:9]=1
Reactant: COS(C)(=O)=O
Reactant: C[n+]1cc[nH]c1
Product: CS(=O)(=O)[O-]
Product: Cn1cc[n+](C)c1
Yield: 169.8 %

Procedure:
Methyl methanesulfonate (5.50 g; 50 mmol) was mixed with 1-methyl imidazolium (4.10 g; 50 mmol) and the reaction mixture was allowed to stand at room temperature (25° C.) for 60 hours. After this period of time, the yellow reaction mixture became solidified. The crystalline mass was crushed, washed two times with ethyl acetate and dried under vacuum, which produced colorless crystals of 1,3-dimethyl imidazolium methanesulfonate (8.16 g, 85% yield), melting point 93.1° C. RMN—1H (CDCl3) δ: 9.81 (1H, s, C—H imidazolium); 7.43 (2H, s, C—H imidazolium); 4.02 (6H, s, NCH3); 2.79 (3H, s, CH3SO3). RMN—13C (CDCl3) δ: 138.5 and 123.3 (C—H imidazolium); 39.4 (CH3SO3); 36.3 (NCH3).
Reaction SMILES: C(N[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH2:20][N:21]([CH3:25])[C:22](=[O:24])[CH3:23])CCCCCCC.[H-].[Na+].BrCCCCCCCCCC=C.CNC(=O)C>CS(C)=O.O>[CH3:25][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10])[C:22](=[O:24])[CH3:23]
Reactant: CCCCCCCCNCCCCCCCCCC(O)CN(C)C(C)=O
Agent: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CNC(C)=O
Solvent: O
Product: C=CCCCCCCCCCN(C)C(C)=O
Reaction time: 8 h
Yield: 57 %

Procedure:
This example illustrates a synthesis of 1-Octylamino-10-hydroxy-11-(N-methylacetamido)undecane (compound no. 77). Sodium hydride (0.56 g, 23 mmol) was added to a solution of 1-bromo-10-undecene (5.4 g, 23 mmol) and N-methylacetamide (91.7 g, 23 mmol) in DMSO (40 mL). After 8 hours, the reaction was complete and the mixture added to water (100 mL) and extracted with dichloromethane (3×100 mL). The combined extracts were washed with water (70 mL) and saturated aqueous salt solution (70 mL), and dried over sodium sulfate. The solvent was evaporated under vacuum to give a yellow residue, which was chromatographed (silica/ethyl acetate), yielding 2.95 g of 1-(N-methylacetamido)-10-undecene as a colorless oil (57% yield).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:24]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:25]([NH:27][N:28]([S:35]([CH3:38])(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClCCl>[OH:7][NH:8][C:9]([C@H:11]([C@@H:24]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:25]([NH:27][N:28]([S:35]([CH3:38])(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](C/C=C/c1ccc([N+](=O)[O-])cc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](C/C=C/c1ccc([N+](=O)[O-])cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A solution of 0.080 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-(4-nitrophenyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in a mixture of 3 ml of methanol and 1.5 ml of dichloromethane was treated with 0.020 g of 4-toluenesulphonic acid. The mixture was stirred for 5 hours at room temperature and the solution was evaporated. The resulting gum was triturated with diethyl ether to give 0.063 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-(4-nitrophenyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a light-brown solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[CH:12]=[C:11]([CH:13]=[C:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)[O:10][N:9]=1.[CH3:20]N1CCC(=O)C1.CC1C=C(C[Si](C)(C)C)ON=1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][C:8]1[CH:12]=[C:11]([CH:13]=[C:14]2[CH2:18][CH2:17][CH2:20][N:16]([CH3:19])[CH2:15]2)[O:10][N:9]=1
Reactant: Cc1cc(C=C2CCN(C)C2)on1
Reactant: CN1CCC(=O)C1
Agent: Cc1cc(C[Si](C)(C)C)on1
Agent: O=C(O)C(=O)O
Product: Cc1cc(C=C2CCCN(C)C2)on1

Procedure:
3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrolidine oxalate, compound 8, and (E) 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrrolidine oxalate, compound 9, starting form 1-methyl-pyrrolidin-3-one (J. Amer. Chem. Soc., 55, 1933, 1233-1241) and 3-methyl-5-trimethylsilylmethyl-isoxazole.
Reaction SMILES: N[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].N(OCCCC)=O.C(Br)(Br)[Br:24]>>[Br:24][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCCn1cnc(C(=O)OCC)c1N
Reactant: BrC(Br)Br
Agent: CCCCON=O
Product: CCCCn1cnc(C(=O)OCC)c1Br
Yield: 46 %

Procedure:
To a solution of ethyl 5-amino-1-n-butyl-1H-imidazole-4-carboxylate (0.05 g, 0.24 mmol) in bromoform (5 mL) was added butyl nitrite (0.10 mL, 0.71 mmol). The reaction mixture was stirred at reflux for 5 h. After an aqueous work up, extracting with ethyl acetate, the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ether/hexane) of the residue gave the title compound as an oil (0.03 g, 46%). 1H NMR (250 MHz, CDCl3) δ 7.50 (b, 1H), 4.41 (q, 2H), 3.95 (t, 2H), 1.70 (quintet, 2H), 1.40 (m, 5H), 1.00 (t, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([C:12]2[C:20]3[C:15](=[C:16]([O:26][CH3:27])[N:17]=[C:18]([C:21]#[C:22][CH2:23][CH2:24][OH:25])[CH:19]=3)[N:14]([CH3:28])[CH:13]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[OH:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:11][C:10]=1[C:12]1[C:20]2[C:15](=[C:16]([O:26][CH3:27])[N:17]=[C:18]([C:21]#[C:22][CH2:23][CH2:24][OH:25])[CH:19]=2)[N:14]([CH3:28])[CH:13]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(C#CCCO)cc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nc(C#CCCO)cc23)c1
Yield: 60.1 %

Procedure:
A mixture of Example 126B (50 mg, 0.120 mmol), 2,4-difluorophenol (15.62 mg, 0.120 mmol) and cesium carbonate (58.7 mg, 0.180 mmol) in dimethylsulfoxide (0.5 mL) was heated at 120° C. in a microwave oven (Biotage Smith Synthesizer) for 45 minutes. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were washed with water (2×), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was absorbed on silica gel and purified by flash chromatography (silica gel, 20-90% ethyl acetate/heptanes) to give the title compound (38 mg, 60% yield)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]12[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]1[CH2:24][NH:23][CH2:22]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:29][C:27]([CH:26]1[CH:25]2[CH:21]1[CH2:22][N:23]([C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=1)=[O:14])[CH2:24]2)=[O:28])[CH3:31]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCOC(=O)C1C2CNCC21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1C2CN(C(=O)c3ccc(N4CC(F)(F)C4)c(OCC4CC4)n3)CC21

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate (179236-79-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=422.5 [MH+].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([NH2:29])=O)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1.[C:54]([O:59][CH2:60][CH3:61])(=[O:58])[C:55]#[C:56][CH3:57]>O1CCCC1.C1(C)C=CC=CC=1.C(P(CCCC)CCCC)CCC>[CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=2)[NH:15][C:14]([C:27]2[S:41][CH:56]([CH2:55][C:54]([O:59][CH2:60][CH3:61])=[O:58])[CH2:57][N:29]=2)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC#CC(=O)OCC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCC4CCOCC4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
5-[4-(Methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indole-2-carboxamide (500 mg) was dissolved in tetrahydrofuran (20 mL), Lawesson's reagent (455 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80 to 70:30, volume ratio) to give a yellow oil. The obtained yellow oil was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-toluene (15 mL), ethyl 2-butynoate (0.26 mL) and tributylphosphine (0.30 mL) were added, and the mixture was stirred at 50° C. for 2.5 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90 to 100:0, volume ratio) to give the title compound (310 mg, yield 48%) as an orange oil. MS 573 (MH+).