Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.[H-].[Na+].P([O-])([O-])([O-])=O>CN(C=O)C.O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: BrCCCCCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCBr)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (5.00 g) and 1,6-dibromohexane (9.26 ml) in DMF (50 ml) at 0° under nitrogen was treated in three equal portions with sodium hydride (60% dispersion in mineral oil, 963 mg). The mixture was stirred at 0° for 30 min and then at 20° for a further 2.5 h. Phosphate buffer solution (pH 6.5, 50 ml) and water (150 ml) were added and the mixture was extracted with diethyl ether (2×150 ml). The combined extracts were washed with water (2×150 ml) and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-dichloromethane (1:4) gave the title compound (7.10 g). LCMS RT=3.52 min, ES +ve 412 (MH)+, 414 (MH)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CS(C)=O>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:10]1.[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][O:15][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C@@H:11]([OH:12])[CH2:10]1
Reactant: Clc1ccccn1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COc3ccccn3)O2)cc1F
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](Oc3ccccn3)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 0.70 g quantity of sodium hydride (60%, dispersion in mineral oil) was added to a solution of 2.00 g of 2'-deoxy-5-fluorouridine in 10 ml of dimethyl sulfoxide. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 0.91 ml of 2-chloropyridine. Then the mixture was stirred at 80° C. for 3 hours. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate and 30 ml of water. The solution was made into a weak acidic solution by addition of 6N-hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using 1- 2% methanol-chloroform as an eluent, giving 2'-deoxy3',5'-0-di-(2-pyridyl)-5-fluorouridine (Example 46), 2'-deoxy-5-fluoro-3'-O-(2-pyridyl)uridine (Example 47) and 2'-deoxy-5-fluoro- 5'-O-(2-pyridyl)uridine (Example 48).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([S:25][C:26]2[N:30]=[CH:29][NH:28][N:27]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45]C(C)([O-])C.[K+].CI.Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([S:25][C:26]2[N:30]=[CH:29][N:28]([CH3:45])[N:27]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](Sc2nc[nH]n2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cnc(S[C@H]2[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]2OCc2ccc(Cl)c(Cl)c2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
Dissolve di-tert-butyl (1R,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.60 g, 0.893 mmol) in anhydrous tetrahydrofuran (3.6 mL) in a flame-dried flask and cool to −78° C. Add potassium t-butoxide (0.80 g, 0.893 mmol) and stir for 15 minutes. Add methyl iodide (0.127 g, 0.893 mmol, pretreated by filtration through basic alumina) and allow to stir at −78° C. for 15 minutes. Allow the mixture to warm to room temperature and then stir for 30 minutes at room temperature. Pour crude reaction mixture into water and adjust pH to 6 with 1N aqueous HCl and extract into ethyl acetate. Dry the organic layer over magnesium sulfate, filter and concentrate under reduced pressure. Purify by reverse phase flash chromatography (100 g C18 column eluting with 45-95% Acetonitrile/Water (with 0.1% trifluoroacetic acid in both), compound elutes at 89% Acetonitrile). Combine the desired fractions and neutralize with aqueous bicarbonate. Extract with ethyl acetate, dry the organic layer over magnesium sulfate, filter and concentrate under reduced pressure to yield the title compound as a white foam (0.16 g, 0.23 mmol, 26%): MS (m/z): 473/475/477 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:5][CH2:6][N:7]1[C@H:12]2[CH2:13][CH2:14][C@@H:8]1[CH2:9][CH:10]([N:15]1[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][N:17]=[C:16]1[CH3:23])[CH2:11]2)[CH2:3][NH2:4].C(N(C(C)C)CC)(C)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:1][C:2]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH2:5][CH2:6][N:7]1[C@H:8]2[CH2:14][CH2:13][C@@H:12]1[CH2:11][CH:10]([N:15]1[C:19]([CH:20]([CH3:22])[CH3:21])=[N:18][N:17]=[C:16]1[CH3:23])[CH2:9]2)[CH2:3][NH:4][S:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:47])=[O:46]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of intermediate 24 (158 mg, 0.4 mmol) in CH2Cl2 (4 mL) was added diisopropylethylamine (0.175 mL, 1.0 mmol) followed by phenylsulfonyl chloride (0.065 mL, 0.5 mmol) and the solution stirred at room temperature under nitrogen atmosphere for 18 h. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with 0-5% methanol/CH2Cl2 to give the title compound (150 mg, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][O:19][C:20]4[CH:27]=[C:26]([CH2:28][NH2:29])[CH:25]=[CH:24][C:21]=43)[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1.[O-:31][C:32]#[N:33].[K+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[N:23]=[C:22]3[C:21]4[CH:24]=[CH:25][C:26]([CH2:28][NH:29][C:32]([NH2:33])=[O:31])=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:12][C:11]([CH3:30])=[N:10]1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(CN)cc2OCC3)n(-c2ccc(F)cc2F)n1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CNC(N)=O)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
C-{2-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-methylamine in acetic acid and water was reacted with potassium cyanate in water to give 354. MS (ESI+) 452.1. 1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.68 (td, J=8.7, 6.2 Hz, 1H), 7.62-7.54 (m, 2H), 7.32-7.25 (m, 1H), 6.87-6.80 (m, 2H), 6.44 (t, J=6.1 Hz, 1H), 5.57 (br, 2H), 4.49-4.38 (m, 4H), 4.12 (d, J=6.1 Hz, 2H), 2.35 (s, 3H)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20]([F:25])([F:24])([F:23])([F:22])[F:21])[CH:13]=1.O.[NH2:27]N.[CH2:29](O)[CH3:30]>>[NH2:3][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20]([F:25])([F:21])([F:22])([F:23])[F:24])[CH:13]=1.[CH2:29]([N:3]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:20]([F:24])([F:25])([F:21])([F:22])[F:23])[CH:13]=1)[C:4](=[O:11])[C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([NH2:27])=[O:1])[CH3:30]
Reactant: N#Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1S(F)(F)(F)(F)F
Reactant: NN
Reactant: CCO
Solvent: O
Product: CCN(C(=O)c1ccccc1C(N)=O)c1ccc(C#N)c(S(F)(F)(F)(F)F)c1
Product: N#Cc1ccc(N)cc1S(F)(F)(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
610 mg (1.63 mmol) of 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-pentafluorosulfanylbenzonitrile 51.8 were dissolved in 30 ml of ethanol and admixed with 100 mg (1.956 mmol) of hydrazine hydrate (100%). The mixture was stirred at room temperature overnight. Thereafter, the mixture was concentrated under reduced pressure and the residue was purified by chromatography (preparative HPLC; Purospher STAR RP-18e (10 μm); eluent: acetonitrile/water (0.5% trifluoroacetic acid) 5/95→95/5 [45 min.]). 4-Amino-2-pentafluorosulfanylbenzonitrile 51.9 (1H NMR: 7.65, s, 1H, 7.2, s, 1H, 6.8, m, 3H) and N-(4-cyano-3-pentafluorosulfanylphenyl)phthalamide ethyl ester 51.10 (1H NMR: 11.3, s, 1H, 8.6, s, 1H, 8.2, d, 1H, 8.1, d, 1H, 7.95, d, 1H, 7.75, m, 1H, 7.7, m, 2H, 4.2, q, 2H, 1.15, t, 3H) were obtained.
Reaction SMILES: [CH2:1]([CH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:10]=2[O:9][C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:25].[K+]>CO>[OH:9][C:10]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([OH:24])=[O:25]
Reactant: [OH-]
Reactant: CCCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Agent: [K+]
Solvent: CO
Product: CCCCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O

Procedure:
3-n-Hexyl-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(o-tolyloxy)phenyl]n-octanoic acid, mp. 65°-66° C.
Reaction SMILES: [NH3:1].[Na].[S:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1.[Cl-].[NH4+].O1[CH2:16][CH2:15]CC1>C(#N)C>[NH2:9][C:8]([C:5]1[CH:6]=[CH:7][S:3][CH:4]=1)=[CH:15][C:16]#[N:1]
Reactant: C1CCOC1
Reactant: N
Reactant: N#Cc1ccsc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CC#N
Product: N#CC=C(N)c1ccsc1
Reaction time: 0.75 h

Procedure:
A 500 ml., three-necked flask is equipped with a mechanical stirrer, gas inlet, dry ice condenser, potassium hydroxide drying tube and addition funnel. A 100 ml. portion of ammonia is condensed into the flask and a pellet of sodium is added. When the dark blue colors persists, ferric chloride is added discharging the color to brown. A 3.2 g. portion of sodium is added and the mixture is allowed to stand for 45 minutes. A 5.7 ml. portion of acetonitrile in 10 ml. of tetrahydrofuran is added and the reaction is stirred for 20 minutes. The reaction is cooled in a dry ice-acetone bath and 10.9 g. of 3-thiophenecarbonitrile in 25 ml. of tetrahydrofuran is added. The reaction is stirred in the cold bath for 90 minutes and then heated at reflux for 3 hours. A 7.4 g. portion of ammonium chloride is added and the mixture is allowed to evaporate overnight. A 100 ml. portion of water and 100 ml. of chloroform are added and the mixture is filtered. The aqueous phase is extracted with chloroform, the combined organic solution is washed once with water, dried over magnesium sulfate and filtered through Magnesol. The filtrate is evaporated in vacuo to an orange oil. A 30 ml. portion of benzene is added and then petroleum ether until the mixture is cloudy. Cooling produces a precipitate which is collected and recrystallized from benzene giving the desired product as a solid, mp. 67°-69.5° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6](O)[CH2:5][C:4]1=[O:57])[CH3:2].C(N(C(C)C)CC)(C)C.[N+](C1C=CC=CC=1S(Cl)(=O)=O)([O-])=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]=[CH:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Agent: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC

Procedure:
To a solution of 404.5 mg of 17-ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone, 64.8 mg 4-dimethylaminopyridine, 87.1 μl of diisopropyl ethyl amine and 4 ml methylene chloride stirred magnetically at 0° C. was added 113.2 mg o-nitrophenylsulfonyl chloride in 2 ml methylene chloride. At 19 hours the mixture was evaporated and purified by thin layer chromatography on silica gel using hexane/acetone mixtures (60/40 and 50/50) as eluent. The faster moving compound, 155 mg, was repurified on silica gel preparative thin layer chromatography using ethyl acetate as eluent. The slower moving compound, 69.8 mg, was identified as 17-ethyl-1,20-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[N+:20]([C:17]1[N:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1)([O-:22])=[O:21].[C:25]([OH:27])([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester obtaine above (0.821 g, 0.27 mmol) in 10 mL of a 1:4 mixture of trifluoroacetic acid and dichloromethane was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to yield 1-(6-nitropyridin-3-yl)piperazine as a brown oil (0.086 g, TFA salt, 100% yield). MS (ES+) m/z 209.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[CH:5]=[N:6][C:7]=1Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>CC(C)CO>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([O:11][CH2:9][CH:4]([CH3:5])[CH3:3])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:9]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])=[O:11])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: CC(C)CO
Product: CC(C)COc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31, using 5-bromo-6-chloro-3-pyridinecarboxylic acid, 2-methyl-1-propanol (commercially available), 4-chlorophenyl-boronic acid (commercially available), and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials. MS (ISP): 403.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(C)C=CC=CC=1>O1CCCC1>[F:24][C:25]([F:35])([F:36])[C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.969 mmol), 3-(trifluoromethyl)phenyl isocyanate (667 μL, 4.84 mmol), toluene (4 mL) and tetrahydrofuran (1 mL) was stirred with heating under reflux for 3 hr. After the reaction mixture was allowed to cool to room temperature, the precipitate was collected by filtration and washed with ethyl acetate/diisopropyl ether to give the title compound (268 mg, 56%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:13][CH:14]([F:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH2:15][CH:14]([F:17])[F:13]
Reactant: NCC(F)F
Reactant: Clc1nc2ccncc2nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)CNc1nc2ccncc2nc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (50 mg, 0.250 mmol) in dioxane (250 μL) was treated with 2,2-difluoroethanamine (21.0 μL, 0.275 mmol) and DIPEA (131 μL, 0.750 mmol). The resulting reaction mixture was stirred at 70° C. for 1 h then purified by flash silica gel chromatography using a gradient of 0% to 60% EtOAc in hexanes to give the title compound (52 mg, 85%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17].[CH2:21]([NH2:24])[C:22]#[CH:23]>>[N+:16]([CH:15]=[C:14]([NH:24][CH2:21][C:22]#[CH:23])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[Br:1])([O-:18])=[O:17]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1[nH]cnc1Br
Reactant: C#CCN
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br

Procedure:
When 2-[(4-bromo-1H-imidazol-5-yl)methylthio]ethylamine (prepared according to the procedure described in Belgian Pat. No. 779,775]) is reacted with 1,1-bis(methylthio)-2-nitroethylene according to the procedure of Example 6, Step A, and the resultant 1-nitro-2-methylthio-2-{2-[(4-bromo-1H-imidazol-5-y;)methylthio]ethylamino}ethylene is treated with propargylamine by the procedure of Example 6, Step B, the title compound is produced.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C.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.O>[C:11]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1cncc(Br)c1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1cncc(-c2ccccc2)c1
Yield: 67.2 %

Procedure:
Preparation H2, Step 1: 5-bromonicotinic acid (500 mg, 2.48 mmol, 1 eq.), phenylboronic acid (454 mg, 3.71 mmol, 1.5 eq.), tetrakis(triphenylphosphine)palladium(0) (143 mg, 0.124 mmol, 0.05 eq.), and sodium carbonate (787 mg, 7.43 mmol, 3 eq.) were mixed in ethanol (5 mL), toluene (25 mL), and water (5 mL) at room temperature under nitrogen. The reaction was then refluxed for 20 hours. Worked up by adding water then stripping off the ethanol. Rinsed the aqueous layer 2 times with diethyl ether. Adjusted the aqueous layer pH=3 with conc. HCl. The acidic aqueous layer was extracted 3 times with ethyl acetate and a little THF. The ethyl acetate/THF layers were combined, dried over sodium sulfate and stripped to give 5-phenylnicotinic acid (332 mg) as a white solid. Yield=67%. LCMS detects (M+H)+=198.1.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13](=O)O[C:10]2=[O:11].CS(C)=O>O>[CH3:13][N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[C:10](=[O:11])[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 12.3 g. of L-proline, 17.7 g. of N-mthyl isatoic anhydride and 100 ml. of dimethyl sulfoxide is heated on a steam bath for 40 minutes. The mixture is cooled and diluted with 250 ml. of cold water. The precipitate is recovered by filtration, washed with water and then ether, air dried and then recrystallized from ethanol yielding the intermediate L-1-(N-methylanthrailoyl)proline, melting point 140°-142°C., [α]D25 -165°C. (1.1%, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22]I.[N-:30]=[N+:31]=[N-:32].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:30]([CH2:22][C@@H:7]1[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9](=[O:10])[N:6]1[CH2:5][C:4]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=1[O:2][CH3:1])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CI)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN=[N+]=[N-])c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-(iodomethyl)-4-oxoazetidin-3-yl)carbamate (5.00 g, 9.80 mmol) in THF (100 mL) at 0° C. was added TEA (2.73 g, 19.6 mmol) followed by a solution of tetrabutylammonium azide (3.62 g, 12.7 mmol) in THF. After stirring at rt for 16 h, it was filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 2%), affording the title compound (3.4 g, 81%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:20]>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: N#Cc1cc(Br)cc(N2CCC(C(=O)O)CC2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(c2cc(Br)cc(C#N)c2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-bromo-5-cyanophenyl)piperidine-4-carboxylic acid (1.1 g, 3.6 mmol) in toluene (4 mL) and methanol (2 mL) was added TMSCHN2 (2 M in Et2O, 3.5 mL, 7.0 mmol) dropwise at room temperature. After 1 h, the reaction was quenched with acetic acid (˜0.1 mL), diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was separated, dried (MgSO4), and concentrated to give methyl 1-(3-bromo-5-cyanophenyl)piperidine-4-carboxylate in ˜100% yield.