Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].[CH3:5][N:6]1[C:10]([C:11]2[O:15][CH:14]=[N:13][C:12]=2[CH3:16])=[N:9][NH:8][C:7]1=[S:17].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CCO>[Cl:22][CH2:21][CH2:20][CH2:19][S:17][C:7]1[N:6]([CH3:5])[C:10]([C:11]2[O:15][CH:14]=[N:13][C:12]=2[CH3:16])=[N:9][N:8]=1
Reactant: ClCCCBr
Reactant: Cc1ncoc1-c1n[nH]c(=S)n1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ncoc1-c1nnc(SCCCCl)n1C
Temperature: 25 °C

Procedure:
This material (498 g, 1 wt) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled to 0° C. DCC (1.62 wt, 1 eq) was added portionwise followed by HOBt (1.07 wt, 1 eq). The mixture was warmed to 25±2° C. and stirred for 30 min. 4-Methyl-3-thiosemicarbazide (0.83 wt, 1 eq) was then added and the mixture further stirred for 2 h at 25±2° C. The mixture was filtered and the cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70° C. for 30 min. After this time, the mixture was cooled to 25±2° C. and a solid was removed by filtration. The cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0° C. and acidified to ca. pH 5 with HCl (aqueous, 16%; NOTE: keep temperature while adding HCl below +10° C.). The suspended product was isolated by filtration washing with water (2×3 vol). The cake was dried at 40° C. for 18 h in high vacuum to obtain 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 37%). NaOEt (21% solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25±2° C. until a clear solution was obtained. Then 1-bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40° C. for 24 h then cooled to 25° C. After filtration water (20 vol) was added and the ethanolic phase was removed by vacuum distillation (internal temperature ˜40° C.). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32](C3C=CC(Br)=CN=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][N:3]=3)=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Reactant: FC(F)(F)c1ccc(Nc2cnc(Br)cn2)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: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 130 °C

Procedure:
A solution of (5-Bromo-pyrazin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (0.072 g) and {4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.087 g) in 2 Ml DME was charged with 2 M sodium carbonate (1 Ml) and Pd(PPh3)4 (0.027 g, 0.1 equiv). The biphasic mixture was sparged with nitrogen for 3 min, then stirred at 130° C. under microwave heating for 30 min. The reaction was partitioned between EtOAc and water, and the organic extracts were dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography (33% EtOAc in hexanes) afforded the title compound: (M+H)+ 471.2.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[O:22][C:21]([F:20])([F:31])[F:32])[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and 2-(trifluoromethoxy)benzaldehyde (0.09 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (69 mg).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=O.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([N:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1)=[O:13]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1nc(-c2cc(C(=O)O)ccc2C)c(Cl)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.9 %

Procedure:
A mixture of 3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoic acid (compound 7.3, ˜0.038 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 8.6 mg, 0.044 mmol), EDCI (12 mg, 0.063 mmol), HOBt (8 mg, 0.044 mmol) and DIEA (28 μl, 0.16 mmol) in DMF (1 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with brine (how much), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (8% MeOH in DCM) to yield the title compound as a foam (2.8 mg, 19% over 2 steps). m/z (ES+) 391 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.54-7.40 (m, 3H), 7.37 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.80-4.58 (m, 2H), 4.41-4.19 (m, 2H), 4.03-3.92 (m, 1H), 2.49 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C1([C:17]([O-:19])=[O:18])C(C)=CC=CC=1O.[K+].C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 80 %

Procedure:
A pressure vessel was charged with 6.98 g of potassium phenolate, 7.54 g of potassium meta cresolate and 25 g of NeoSK 1400. With stirring at 1,000 r.p.m., reaction was carried out at a carbon dioxide pressure of 7 kg/cm2 (G) and at 300° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 80.0% on the basis of potassium phenolate, with 3.6% salicylic acid forming as a by product.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[CH2:22][CH2:21][C:20]([CH:23]=O)=[C:19](Cl)[CH2:18][CH2:17]1>O1CCOCC1>[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:2]([C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[O:3][C:19]=2[CH2:18][CH2:17]1
Reactant: CCCCOC(=O)CO
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1cc2c(o1)CCN(Cc1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 gm (0.015 mol) of butyl glycolate were slowly added dropwise, while vigorously stirring, to a suspension of 0.72 gm (0.015 mol) of 50% sodium hydride in 10 ml of absolute dioxane at room temperature while dry nitrogen was introduced. The temperature of the intensely foaming reaction mixture was kept below 30° C. by cooling with ice-cold water, as needed. After 11/2 hours of stirring at room temperature, a solution of 2.84 gm (0.010 mol) of 1-(2-chlorobenzyl)-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine in 20 ml of absolute dioxane was added dropwise, whereupon the temperature of the reaction mixture rose from 20° C. to about 33° C. Then, the mixture was stirred for two hours at room temperature, poured into about 150 ml of ice-cold water, and the aqueous mixture was extracted three times with ethyl acetate. The combined organic phases were extracted with water three times, dried over sodium sulfate and concentrated by evaporation. The residue was purified by column chromatography on silicagel, using chloroform/ethyl acetate (93:7) as eluant.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.N[CH2:10][C@@H:11]1CC[CH2:13][N:12]1CC.C(=O)C>>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:4]1
Reactant: CCN1CCC[C@H]1CN
Reactant: CN(C)[C@@H]1CCNC1
Agent: CC=O
Product: CNCCN1CC[C@@H](N(C)C)C1

Procedure:
By using (3R)-(+)-3-(dimethylamino)pyrrolidine (200 mg) as a starting material, the title compound (123 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.I[CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[C:27]([F:29])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[C@H:18]([OH:30])[C@@H:17]1[OH:31].CO>C1(C)C=CC=CC=1>[F:29][C:27]1[C:25](=[O:26])[NH:24][C:22](=[O:23])[N:21]([CH:28]=1)[C@@H:19]1[O:20][C@H:16]([CH3:15])[C@@H:17]([OH:31])[C@H:18]1[OH:30]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O

Procedure:
When the reduction is carried out by using tributyltin hydride, the reaction takes place by dissolving 5′-deoxy-5′-iodo-5-fluorouridine in an alcohol, for example methanol, the reducing agent being added as a solution in an organic solvent, for example in toluene, and the mixture is heated at reflux in the presence of α,α′-azoisobutyro nitrile in catalytic amount. After 1÷3 hours the reduction is complete and, after evaporation of the solvent, the 5′-deoxy-5-fluorouridine thus obtained is recovered according to conventional methods.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40]/[CH:41]=[CH:42]/[C:43]([O:45]C(C)(C)C)=[O:44])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH2:40]/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC/C=C/C(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC/C=C/C(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(trans-3-tert-butoxycarbonylallyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.4 g) and anisole (4.4 ml) in methylene chloride (9.0 ml) was added trifluoroacetic acid (17.6 ml) under ice-cooling, and the mixture was stirred at ambient temperature for 2 hours. To the reaction mixture was added diisopropyl ether, and the precipitated substance was collected by filtration, which was washed with diisopropyl ether. To this substance were added ethyl acetate and water, and then adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated aqueous layer was washed with ethyl acetate, and the remaining ethyl acetate in the aqueous solution was completely removed by evaporation, followed by adjusting to pH 2.2 with 10% hydrochloric acid. The precipitated substance was collected by filtration and then dried to obtain 7-[2-(2-aminothiazol-4-yl)-2-(trans-3-carboxyallyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.31 g).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[CH:12]1([C:15]([CH3:17])=[O:16])[CH2:14][CH2:13]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:12]1([C:15](=[O:16])[CH2:17][C:4]([C:6]2[N:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cccnn1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1cccnn1

Procedure:
A stirred mixture of 4.0 g. of ethyl-3-pyridazinecarboxylate, 4.4 g. of cyclopropylmethyl ketone and 1.6 g. of sodium methoxide in 100 ml. of benzene is heated under reflux for 5 hours. The mixture is diluted with 300 ml. of water and the benzene phase is separated. The aqueous mixture is made weakly acidic with dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to yield straw-colored crystals which are recrystallized from acetonitrile to give cream-colored crystals, melting point 85°-87°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([O:30]C)=O)[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:33][NH2:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([NH:34][CH3:33])=[O:30])[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Reactant: CN
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Yield: 97 %

Procedure:
In a similar manner to that described in example 196, from methyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.115 mmol) and methylamine was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-methyl-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (48 mg, 97% yield) as a white solid. 1H NMR (CDCl3) δ 9.96 (s, 1 H), 8.48 (s, 1 H), 7.11-7.05 (m, 4 H), 7.01-6.98 (m, 4 H), 6.77 (s, 1 H), 3.92 (s, 2 H), 3.87 (s, 3 H), 2.95 (d, J=4.8 Hz, 3 H); HRMS m/z calcd for C24H21FN3O4: 434.1511 Found: 434.1512.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:47][CH:48]=[CH:49][N:50]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:41]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:50][CH:49]=[CH:48][N:47]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54][C:24]2[S:25][CH:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[N:41]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccsc1Cl
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: O=[N+]([O-])c1ccsc1NCCNc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(3-nitro(2-thienyl))amino]-ethyl}amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-3-nitrothiophene in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[N:22]=[C:23]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[C:24]4[S:29][C:28]([CH2:30][N:31]5[CH2:42][CH2:41][C:34]6([O:39][CH2:38][C:37](=[O:40])[NH:36][CH2:35]6)[CH2:33][CH2:32]5)=[CH:27][C:25]=4[N:26]=3)=[CH:13]2)(=O)=O)C=CC=CC=1>O1CCOCC1>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[N:22]=[C:23]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[C:24]3[S:29][C:28]([CH2:30][N:31]4[CH2:42][CH2:41][C:34]5([O:39][CH2:38][C:37](=[O:40])[NH:36][CH2:35]5)[CH2:33][CH2:32]4)=[CH:27][C:25]=3[N:26]=2)=[CH:13]1
Reactant: O=C1COC2(CCN(Cc3cc4nc(-c5cn(S(=O)(=O)c6ccccc6)c6ccccc56)nc(N5CCOCC5)c4s3)CC2)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1COC2(CCN(Cc3cc4nc(-c5c[nH]c6ccccc56)nc(N5CCOCC5)c4s3)CC2)CN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
A degassed solution of 9-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (150 mg, 0.34 mmol), 1-(phenylsulfonyl)-3-indoleboronic acid (155 mg, 0.51 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and Cs2CO3 (225 mg, 0.69 mmol) in a mixture of 1,4-dioxane (6 mL) and water (3 mL) was subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to give 9-[2-(1-benzenesulfonyl-1H-indol-3-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one as a crude oil. Aqueous NaOH (12.5 M, 0.4 mL) was added to a solution of 9-[2-(1-benzenesulfonyl-1H-indol-3-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 90 min, and then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to afford a sticky solid. The solid was purified by flash chromatography (Si-PPC, DCM: MeOH, 100:0 to 99:1 to 95:5) followed by reverse phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 90:10 to 5:95) to afford 116 as a white solid (72 mg, 40%). LCMS: RT=5.05 min, [M+H]+=519.2. 1H NMR (CDCl3, 400 MHz): δ 8.69-8.64 (m, 1H); 8.45 (s, 1H); 8.15 (d, J=2.7 Hz, 1H); 7.44-7.40 (m, 1H); 7.30-7.22 (m, 3H); 5.91 (s, 1H); 4.17 (s, 2H); 4.08-4.03 (m, 4H); 3.94-3.89 (m, 4H); 3.85 (s, 2H); 3.26 (d, J=2.6 Hz, 2H); 2.78-2.69 (m, 2H); 2.47 (t, J=11.2 Hz, 2H); 1.96 (d, J=13.8 Hz, 2H); 1.77-1.67 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32]C)=O)[CH2:7]1.[OH:37][NH2:38].Cl.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([NH:38][OH:37])=[O:32])[CH2:7]1
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](Oc2cccc(F)c2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of dimethyl(2S,3S,5S)-5-(3-fluorophenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (27 mg, 0.000054 mol) in methanol (0.2189 mL, 0.005405 mol) was added 1.640 M of N-hydroxyamine in Methanol (0.659 mL) made from the corresponding HCl salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (18 mg 54.5%). MS (ESI): (M+H)+=501.2.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14].O>CN(C=O)C>[F:1][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)F)c(C=O)c1F
Temperature: 150 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
96.3 g (1660 mmol) of spray-dried potassium fluoride were carefully dried under high vacuum. 129.2 g (664 mmol) of 5-chloro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (II-1) in 1 L of DMF were added. The reaction mixture was heated to 150° C. with rapid stirring. The reaction is complete after 3 hours (GC check). The reaction mixture is cooled down to room temperature and bulked with water to a total volume of 4 L. The reaction mixture is washed twice with 2000 ml of ethyl acetate each time. The combined organic phases were subsequently washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to obtain 117.6 g (90% of theory, purity 90%) of 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (IV-1) in the form of a brown solid which is further reacted without further purification.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].CN(C)C=O.Br[CH:18]([CH3:20])[CH3:19]>O>[CH3:19][CH:18]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH3:20]
Reactant: CC(=O)C1=CNCCC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C1=CN(C(C)C)CCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-acetyl-1,4,5,6-tetrahydropyridine (20.0 g, 0.16 mole) was added under nitrogen to a mixture of sodium hydride (5.76 g, 0.24 mole) and dry dimethylformamide (50 ml) stirring at 0°C. and stirring was continued for 15 minutes 2-Bromopropane (21.5 g, 0.175 mole) was then added dropwise over 15 min, stirring continued for a further hour at 0°C. then overnight at room temperature. The reaction mixture was cautiously added to iced water (100 g) under nitrogen and extracted with diethyl ether (3×100 ml). The combined organic phase was extracted with water (150 ml), dried over magnesium sulphate, concentrated under reduced pressure to give methyl 1-(1-methylethyl)- 1,4,5,6-tetrahydro-3-pyridyl ketone (1). The product was distilled as a pale yellow oil (b.pt 97-98°C./0.5 mm Hg)