Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[S:4]([C:8]1[CH:16]=[CH:15][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)([O-])(=[O:6])=[O:5].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].N1(C2C=CN=CC=2)CCCC1.[N-]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:27])=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18].[S:4]([N:1]=[N+:2]=[N-:3])([C:8]1[CH:16]=[CH:15][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)(=[O:5])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Secondary alcohol 7 was converted to azide 8 through the formation of a secondary nosylate using 4-nitrobenzenesulfonyl chloride and 4-pyrrolidinopyridine in chloroform followed by azide displacement with sodium azide in N,N-dimethylformamide at 50° C. The p-methoxy trityl protecting group was selectively removed using 1% p-toluenesulfonic acid in methylene chloride. Nosylation of the primary alcohol with 4-nitrobenzenesulfonyl chloride and pyridine in chloroform provided azido-nosylate 9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([C:12]3[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:17]=3)[C:6]2=[N:7][CH:8]=1)#[CH:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C.[Cu](I)I>[NH:30]1[CH:2]=[C:1]([C:3]2[CH:4]=[C:5]3[N:11]=[CH:10][N:9]([C:12]4[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=5[F:25])[CH:17]=4)[C:6]3=[N:7][CH:8]=2)[N:32]=[N:31]1
Reactant: C#Cc1cnc2c(c1)ncn2-c1cc(NC(C)=O)cc(-c2ccc(F)cc2F)c1
Reactant: [N-]=[N+]=[N-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)cnc32)c1
Yield: 90 %

Procedure:
A mixture N-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (300 mg, 0.77 mmol), sodium azide (75 mg, 1.15 mmol, 1.5 eq.), copper iodide (14 mg, 0.07 mmol, 0.1 eq.) in DMF was stirred for 16 h at RT. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product which was purified by preparative HPLC to give the product in 90% yield (300 mg).
Reaction SMILES: [CH:1]1([C:4](O)=O)[CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:16])[O:15][C:13](=[O:14])[CH2:12][C:10](=[O:11])[O:9]1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH:1]1([CH2:4][CH:12]2[C:13](=[O:14])[O:15][C:8]([CH3:16])([CH3:7])[O:9][C:10]2=[O:11])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(=O)C(CC2CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
To a solution of cyclopropanecarboxylic acid (17.2 g) in methylene chloride (800 mL) were added Meldrum's acid (28.8 g), WSCI.HCl (42.2 g) and 4-dimethylaminopyridine (39.1 g), and the mixture was stirred at room temperature for 18 hr. Water and then hydrochloric acid were added to acidify the reaction mixture, and the aqueous layer was removed by partitioning. Under ice-cooling, acetic acid (114 mL) and then sodium borohydride (18.9 g) were added slowly to the organic layer, and the mixture was stirred at room temperature for 3 days. Water and then hydrochloric acid were added to the reaction mixture, and the aqueous layer was removed by partitioning. The organic layer was concentrated to give a yellow powder. This was washed with ether/hexane to give the title compound (25.8 g) as a yellow powder.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH2:23][CH2:24]Br.O>CN(C)C=O.C(N(CC)CC)C>[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:14]1[CH2:23][CH2:24][N:9]1[CH2:8][CH2:7][C:6]2([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]2)[CH2:11][CH2:10]1
Reactant: BrCCC1COc2ccccc2O1
Reactant: O=C1COC2(CCNCC2)CN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1COC2(CCN(CCC3COc4ccccc4O3)CC2)CN1

Procedure:
A solution of 1-oxa-4,9-diazaspiro[5.5]undecan-3-one (2.5 g.) and 3.0 g. of 2-(1,4-benzodioxan-2-yl)ethyl bromide in 40 ml of dimethylformamide and 10 ml of triethylamine was heated to 70° C. for 3 hours. The mixture was poured into water, extracted with methylene chloride, and the methylene chloride was extracted with aqueous HCl. The aqueous extract was made basic with ammonium hydroxide and extracted with methylene chloride and the methylene chloride layer was evaporated to give 9-[2-(1,4-benzodioxan-2-yl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, m.p. 139°-140° C. The base was converted to the HCl salt of 9-[2-(1,4-benzodioxan-2-yl)ethyl]-1-oxa-4,9-diazaspiro-[5.5]undecan-3-one by dissolution in methanolic HCl and precipitation with ether, m.p. 225°-227° C.
Reaction SMILES: C([O:8][C:9](=[O:29])[CH2:10][C@@H:11]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])C1C=CC=CC=1>O1CCCC1.[Pd]>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][C:12](=[O:13])[C@H:11]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:10][C:9]([OH:29])=[O:8])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)Nc1cccnc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)O)C(=O)Nc1cccnc1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of N-(3-pyridyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid benzyl ester (4.28 g) and 10% Pd—C (0.86 g, 50% wet) in tetrahydrofuran (50 ml) was hydrogenated at atmospheric pressure for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether to give N-(3-pyridyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid (2.55 g).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][CH:13]=1>O>[CH3:21][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 80.1 %

Procedure:
37 g of tert-butanol and then 26 ml of pyridine are added to 39.04 g of p-toluoyl chloride and the reaction mixture is refluxed for 3 hours. After cooling, it is poured into water, extracted with AcOEt, washed with a 1N solution of HCl and then with a 5% solution of sodium hydrogencarbonate, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using hexane and then a hexane/DCM mixture (80/20; v/v) as the eluent to give 38.9 g of the expected product, which is used as such in the next step.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+]>O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(OC)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 107.1 %

Procedure:
(R)-N-(2-(3-(3-Methoxyphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (25 g, 59 mmol) was dissolved into 96% ethanol (275 ml) and a 12 N sodium hydroxide solution (22 ml) was added. The reaction mixture was stirred at room temperature for 3.5 h. The solvent was evaporated in vacuo and dichloromethane was added (250 ml). A concentrated hydrochloric acid solution (29.5 ml) was added with cooling of the reaction vessel in an ice-bath. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give a residue which was dissolved into water (250 ml). The aqueous solution was extracted with toluene (3×50 ml) and diethyl ether (50 ml). The organic extracts were discarded and from the aqueous phase water was evaporated in vacuo to give 25 g (98%) of the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2([O:30][CH3:31])[CH2:28][CH2:27][O:26][CH:25]([CH3:29])[CH2:24]2)[CH:19]=[C:20]([OH:22])[CH:21]=1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][NH:15][C:16]3[CH:17]=[C:18]([C:23]4([O:30][CH3:31])[CH2:28][CH2:27][O:26][CH:25]([CH3:29])[CH2:24]4)[CH:19]=[C:20]([OH:22])[CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: COC1(c2cc(N)cc(O)c2)CCOC(C)C1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: COC1(c2cc(O)cc(NCc3ccc4c(ccc(=O)n4C)c3)c2)CCOC(C)C1
Yield: 46 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (2RS,4RS)-4-(3-amino-5-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran to give (2RS,4RS)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethylamino)-5-hydroxyphenyl]-4-methoxy-2-methyltetrahydropyran in 46% yield, as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.C(OCC)(=O)C>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C1COCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 46.2 %

Procedure:
A mixture of 5-bromo-2-nitro-pyridine (5 g, 24.75 mmol), tetrabutyl ammonium iodide (0.46 g, 1.24 mmol), K2CO3 (3.76 g, 27.22 mmol) and morpholine (2.34 g, 27.22 mmol) in DMSO (50 mL) is stirred at 80° C. in a stem tube for 20 hours. The reaction mixture is diluted with ethyl acetate and filtered. The organic solution is washed with water, dried over MgSO4 and concentrated in vacuo. The residue is triturated with dichloromethane and hexane to afford the title compound as a solid (2.39 g, 46%).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10](O)=O)=[N:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].Cl>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[NH:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:20]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1C(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2[nH]1

Procedure:
1.7 g. of 5-nitro-1-methyl-2-imidazolyl carboxylic acid and 1.08 g. of o-phenylenediamine are heated for 40 minutes in a bomb tube to 180° C. in 10 ml. of 25% hydrochloric acid. After evaporating the reaction mixture to dryness and column chromatography on 100 g. of silica gel with methanol-chloroform 1 : 1, 120 mg. of 2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole is obtained, m.p. 257° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[C:12]=3[N:11]=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9]=2[CH:25]=[CH:26][CH:27]2[O:32]C(C)(C)[O:30][CH:29]([CH2:35][C:36]([O-:38])=[O:37])[CH2:28]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].O>C1COCC1.CO.CC(OC)(C)C.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[C:12]=3[N:11]=[C:10]([CH:22]([CH3:23])[CH3:24])[C:9]=2/[CH:25]=[CH:26]/[C@@H:27]([OH:32])[CH2:28][C@@H:29]([OH:30])[CH2:35][C:36]([OH:38])=[O:37])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=CC1CC(CC(=O)[O-])OC(C)(C)O1)CCCN2S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O)CCCN2S(C)(=O)=O
Temperature: 15 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
A solution of Example 1 Part H, 1,1-dimethylethyl(4R,6S)-(E)-(6-{2-[4-(4-fluorophenyl)-2-isopropyl-8-methanesulfonyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]ethenyl}-2,2-dimethyl-[1,3]dioxan-4-acetate (28.4 g, 0.047 mol) in THF/MeOH (5:2, 315 mL) was cooled to 15° C. An aqueous solution of HCl (6 N, 23.5 mL, 0.141 mol) was added over 15 min. The reaction mixture was stirred at 15° C. for 2.5 h. An aqueous solution of NaOH (2 N, 118 mL, 0.235 mol) was added over 15 min at 15° C. The mixture was stirred for an additional 1 h. Water (80 mL), heptane (80 mL), and MTBE (80 mL) were added, and the two phases were separated. The aqueous phase was acidified with aqueous HCl (3 N) to pH 2.7, then extracted with ethyl acetate (2 times, 160 mL and 80 mL, respectively). The organic phases were combined and Ca(OH)2 (1.82 g, 0.030 mol) was added. The mixture was stirred at room temperature for 16 h. The solvent was removed at 45° C. under reduced pressure until a total volume of 210 mL remained. The resultant solution was heated to 55° C. The solution was cooled to 0° C. over 90 min, while seed crystals of Example 24 compound (34 mg) were added at 10° C. The resulting slurry was stirred at 0° C. for an additional 30 min. Heptane (85 mL) was added over 30 min, and the slurry was stirred for 1 h at 0° C. The solids were collected by filtration. After drying at 70° C. under vacuum, (E)-(3R,5S)-7-[4-(4-fluorophenyl)-2-isopropyl-8-methanesulfonyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid, Ca salt was obtained as a white solid (23.0 g, 93% yield): mp 215-220° C.; 1H NMR (400 MHz, CDCl3) δ 0.98-1.04 (m, 1H), 1.20 (d, J=6.0 Hz, 6H), 1.30-1.37 (m, 1H), 1.76-1.82 (m, 2H), 1.91 (dd, J=8.9, 8.9 Hz, 1H), 2.04 (dd, J=3.6, 3.9 Hz, 1H), 2.29 (t, J=6.4 Hz, 2H), 2.50-2.51 (m, 2H), 3.31-3.38 (m, 1H), 3.58 (s, 3H), 3.60-3.62 (m, 1H), 3.76 (t, J=5.6 Hz, 2H), 4.00-4.04 (m, 1H), 5.27 (dd, J=5.2, 5.7 Hz, 1H), 6.13 (d, J=15.6 Hz, 1H), 7.11-7.17 (m, 2H), 7.20-7.26 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 178.4, 162.6, 160.2, 159.3, 148.7, 140.8, 134.5, 131.3, 131.2, 125.4, 123.0, 117.3, 115.7, 115.6, 69.5, 66.5, 45.6, 45.2, 44.8, 43.9, 32.2, 26.3, 23.6, 23.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](Cl)=[O:26])[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])[CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccnc4)nc23)CC1
Yield: 93.2 %

Procedure:
Beginning with 0.078 gm (0.339 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.127 gm (0.712 mMol) 3-pyridinecarbonyl chloride hydrochloride, 0.106 gm (82%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[CH3:15][NH:16][CH3:17]>C(#N)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([N:16]([CH3:17])[CH3:15])=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: CNC
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Solvent: CC#N
Product: CN(C)C(=C[N+](=O)[O-])NCC1CCOC1
Temperature: 25 °C

Procedure:
A mixture comprising 4.0 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene, 10 ml of 50% aqueous dimethylamine solution and 50 ml of acetonitrile was stirred at room temperature for an hour. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/acetone=1/1) to obtain 2.8 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-dimethylamino-2-nitroethylene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.O[CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH:6]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Brc1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)n2cc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-bromo-1H-pyrazole (200 mg, 1.36 mmol), methyl 4-(1-hydroxyethyl)benzoate (490 mg, 2.72 mmol), and triphenylphosphine (resin bound: 3 mmol/g loading, 907 mg, 2.72 mmol) in THF (5 mL) was stirred for 5 minutes at ambient temperature. Di-tert-butyl azodicarboxylate (627 mg, 2.72 mmol) was added and the reaction mixture was stirred for 24 hours at ambient temperature. The reaction mixture was filtered, and the filtrate was diluted with dichloromethane (25 mL) and TFA (6 mL) and stirred for 30 minutes. The mixture was concentrated under reduced pressure and then diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was separated, washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% diethyl ether/hexanes) to afford methyl 4-(1-(4-bromo-1H-pyrazol-1-yl)ethyl)benzoate. MS ESI calc'd. for C13H14BrN2O2 [M+H]+ 309 and 311. found 309 and 311. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.90 (dd, J=6.5 Hz, 1.5 Hz, 2H), 7.58 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 5.72-5.65 (m, 1H), 3.82 (s, 3H), 1.78 (d, J=7.5 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.COCCOC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[S:24]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Reaction time: 18 h

Procedure:
To a solution of indole-3-carbaldehyde (4.0 g, 27.586 mmol) in 1,2-dimethoxyethane (40 mL) KOH (4.63 g, 82.758 mmol) was added at rt and stirred for 10 min. p-toluene sulfonyl chloride (5.785 g, 30.345 mmol) was added to the solution at rt and stirred for 18 h.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1>ClCCl>[ClH:3].[Cl:5][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(O)c2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(Cl)c2ccccc2)CC1
Yield: 61.7 %

Procedure:
To 4.5 parts of sulfinyl chloride is added dropwise a mixture of 13 parts of N-[1-(2-hydroxy-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide hydrochloride and 260 parts of dichloromethane. Upon completion, the whole is stirred and refluxed for a few hours. The reaction mixture is cooled and the solvent is evaporated. The residue is taken up in 2-propanone. The mixture is filtered and the filtrate is treated with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 9.2 parts (61.7%) of N-[1-(2-chloro-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride; mp. 145.3° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]1[O:16][CH:10]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1>FC(F)(F)C(O)C(F)(F)F>[OH:16][CH:9]1[C:8](=[O:17])[C:7]2[CH:6]=[CH:5][N:4]3[C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=[C:3]3[C:2]=2[NH:1][CH:10]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1
Reactant: Cc1nc2c(N)c(C(=O)C3OC3c3ccsc3)ccn2c1C
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cc1nc2c3c(ccn2c1C)C(=O)C(O)C(c1ccsc1)N3
Reaction time: 19 h
Yield: 6.4 %

Procedure:
1.1 g of 8-amino-7-[2,3-epoxy-1-oxo-3-(3-thienyl)propyl]-2,3-dimethylimidazo[1,2-a]pyridine are dissolved in 20 ml of hexafluoroisopropanol at room temperature, the solvent is stripped off after 19 hours and the residue is purified on silica gel (eluent: methylene chloride/methanol=100/3). 70 mg of the title compound of m.p. 222-25° C. (diethyl ether) are obtained.
Reaction SMILES: [CH2:1]([C@H:8]([NH:40]C(=O)OC(C)(C)C)[CH2:9][C@H:10]([OH:39])[C@@H:11]([NH:26][C:27](=[O:38])[C@@H:28]([NH:33][C:34]([O:36][CH3:37])=[O:35])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:40][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C@H:10]([OH:39])[C@@H:11]([NH:26][C:27]([C@@H:28]([NH:33][C:34](=[O:35])[O:36][CH3:37])[C:29]([CH3:30])([CH3:32])[CH3:31])=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
A solution containing the product from Example 89B (0.302 mmol) in dichloromethane (2.5 mL) was treated with trifluoroacetic acid (2.5 mL), stirred at 25° C. for 16 hours and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ether and dilute ammonium hydroxide, and the organic phase was dried over MgSO4 filtered and concentrated to give the title compound (0.068 g, 42% yield).