Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=O)[C:17]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH3:25])[CH:21]=3)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>CCO.C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[N:30][OH:31])[C:17]([NH:19][C:20]3[S:24][N:23]=[C:22]([CH3:25])[CH:21]=3)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)sn1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(NC(=O)C(=NO)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)sn1
Temperature: 25 °C

Procedure:
A stirred mixture of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(3-methyl-isothiazol-5-yl)-2-oxo-acetamide (0.102 g, 0.25 mmol), hydroxylamine hydrochloride (17 mg, 0.25 mmol), and sodium acetate (0.1 g, 1.2 mmol) in EtOH (3 mL) and THF (3 mL) was heated to reflux for 3 days. After being cooled to rt, the reaction mixture was poured into ice-H2O (20 mL). The precipitated product 2-[1-(4-Chloro-benzyl)-1H-indol-3-yl]-2-hydroxyimino-N-(3-methyl-isothiazol-5-yl)-acetamide was collected by filtration, washed with H2O, and dried in vacuo (95 mg, 90%). 1H NMR (DMSO-d6) δ 2.3 (s, 3H), 5.6 (s, 2H), 6.9 (s, 1H), 7.0-7.5 (m, 7H), 8.1 (d, 1H, J=7), 8.65 (s, 1H). ESMS calcd for (C21H17ClN4O2S): 424.1; found 425.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1cncc(Br)c1
Product: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1

Procedure:
5.1 g (20.9 mmol) of the compound from Example 10A are stirred in 7.2 ml (6.2 g, 41.8 mmol) of dimethylformamide diethyl acetal at a bath temperature of 100° C. for 16 h. After cooling, the mixture is concentrated under reduced pressure, the residue is stirred in diisopropyl ether, and the solid is filtered off and finally washed with diisopropyl ether. The crude product is dried under reduced pressure for 16 h.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[CH:33]=[CH:32][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=1.N1CCCC1>Cl[Pd]Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: OCc1ccc(I)cc1
Agent: Cl[Pd]Cl
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCC#Cc2ccc(CO)cc2)cc1
Yield: 20.5 %

Procedure:
General procedure A was followed using the product from step 3 Example 1 (266 mg, 1.0546 mmol), p-iodobenzylalcohol (156.5 mg, 0.669 mmol), PdCl2 (2.5 mg, 0.014 mmol), pyrrolidine (0.277 mL, 3.34 mmol), water (0.844 mL) to give the title compound (60 mg, 20.5%).
Reaction SMILES: N.[Li].[CH:3]#C.C([SiH2]O[C:11]([CH3:31])(C)[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13]1)(C)(C)C>CS(C)=O.C1COCC1>[CH2:11]([CH:12]1[CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][CH2:17]1)[C:31]#[CH:3]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Reactant: C#C
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C#CCC1CCC(CO)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 3-neck 250 mL-flask equipped with a gas inlet tube and dry-ice condenser was cooled to −78° C. and charged with liquid ammonia (40 mL). To the reaction mixture was added lithium wire (600 mg, 86.4 mmol) generating a deep blue solution. The mixture was allowed to stir for 1 hour. Acetylene, passed through a charcoal drying tube, was added to the ammonia until all the lithium had reacted and the solution turned colorless, at which time the flow of acetylene was stopped, the acetylene-inlet tube and condenser removed and the flask outfitted with a thermometer. DMSO (20 mL) was added and the ammonia evaporated with a warm water bath until the mixture reached a temperature of 30° C. The solution was stirred at this temperature for 2 hours until the solution stopped bubbling. The mixture was cooled to 5° C. and compound 84 (11.25 g, 27.3 mmol), in DMSO (10 mL), was added. The temperature was maintained at 5° C. The mixture was allowed to stir at 5° C. for 0.5 hours. Then the solution was gradually warmed to room temperature and stirred for an additional 18 hours. The brown/black reaction mixture was poured slowly over ice (300 g) and extracted with ether (4×100 mL), dried with anhydrous sodium sulfate, and concentrated in vacuo to yield a yellow oil. The oil was subsequently dissolved in THF (200 mL) and changed to a brownish color upon addition of TBAF hydrate (11.20 g, 35.5 mmol). The solution was allowed to stir for 24 hours under N2 atmosphere. After stirring, the reaction was quenched with water (200 mL) and extracted with ether (3×100 mL). The ether extracts were combined and concentrated in vacuo. The crude product was purified by chromatography, on a silica gel column, eluting with 1:1 ether/petroleum ether to yield 86 (3.91 g, 93%) as a yellow oil. 1H NMR (CDCl3) δ 3.45 (d, J=6.2, 2H), 2.10 (d, J=6.2, 2H), 1.9 (s, 1H), 1.94-1.69 (m, 4H), 1.52-1.34 (m, 2H), 1.16-0.83 (m, 4H); 13C NMR (CDCl3) δ 83.8, 69.5, 69.0, 40.8, 37.7, 32.3, 29.7, 26.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.Cl[C:40]([C:42]([O:45][C:46](=[O:48])[CH3:47])([CH3:44])[CH3:43])=[O:41].Cl>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([S:8]([NH:11][C:40](=[O:41])[C:42]([O:45][C:46](=[O:48])[CH3:47])([CH3:44])[CH3:43])(=[O:9])=[O:10])[CH:7]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1S(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(=O)NS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.5 %

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzenesulfonamide (0.10 g, 0.21 mmol) in dichloromethane (2 mL) was added triethylamine (0.033 mL, 0.23 mmol), 4-dimethylaminopyridine (5 mg, 0.04 mmol) and acetic acid 1-chlorocarbonyl-1-methyl-ethyl ester (0.037 mL, 0.25 mmol). The resulting reaction mixture was stirred at ambient temperature overnight, treated with 0.2 N hydrochloric acid extracted with dichloromethane dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude title compound (0.140 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.N12CCN(CC1)CC2.[N:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: Cn1c(=O)[nH]c2cnc(Cl)nc21
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cl)nc21
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-9-methyl-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 1> (3.0 g) in N,N-dimethylformamide (50 ml) were added 1,4-diazabicyclo[2.2.2]octane (5.5 g) and 1-pyrrolidine carbonyl chloride (2.7 ml) and the mixture was stirred for 1 hour. The reaction mixture was poured into cold water and the crystals precipitated were collected by filtration to give the title compound 3.0 g.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[C:4](=[O:12])[O:3]1.[OH-].[K+].S(=O)(=O)(O)[O-:16].[K+]>O>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:12])[O:3][CH:2]2[OH:16]
Reactant: O=S(=O)([O-])O
Reactant: O=C1OC(Br)c2cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1OC(O)c2cc(Br)ccc21

Procedure:
To a suspension of EXAMPLE 1A (5 g, 17.1 mmol) in water (40 mL) was added powdered potassium hydroxide (1.92 g, 34.3 mmol), and the mixture was refluxed for 1 hour. After cooling, potassium bisulfate (2 g) was added, and the mixture extracted with ethyl acetate (150 mL). The organics were concentrated on a rotary evaporator and dried under vacuum to yield the title compound. MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6]([CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])([O:8][CH2:9][CH3:10])=[O:7].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br)([O-:20])=[O:19]>O>[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][C:11]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])([O-:20])=[O:19]
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCCNC1=O
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.45 g) was added to ethanol (100 ml), to which was added 3-carboethoxy-2-piperidone (10.0 g). The reaction mixture was stirred for 15 minutes, to which was added 2-nitrobenzyl bromide (13.2 g) at room temperature. The reaction mixture was stirred at 60° C. for 3 hours. Water was added to the reaction mixture, which was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the entitled compound (14.6 g).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:21])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]([Cl:20])=[N:9][CH:8]=1.Cl>O1CCCC1.O>[Cl:20][C:10]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:12][C:7]([C:6]([OH:21])=[O:5])=[CH:8][N:9]=1
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
Lithiumhydroxide monohydrate (2.41 g, 57 mmol) was added to a solution of 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester (8.1 g, 29 mmol) in tetrahydrofuran (120 mL) and water (34 mL) under nitrogen at room temperature. The reaction mixture was stirred for 20 h at room temperature, poured onto ice/water (200 g), acidified with 1 N HCl (120 mL) and the whole was extracted with ethyl acetate (250 mL). The water phase was extracted twice with ethylacetate (2×200 mL), organic phases were combined, dried over MgSO4 and concentrated in vacuo. 6-chloro-5-(4-chloro-phenyl)-nicotinic acid was isolated as a colorless solid and used without further purification; 7.30 g (94% yield). m/z (ISP−): 266.1 (M−H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[O:17])=[CH:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]1COCC1.C[Mg]Br>Cl.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)([OH:17])[CH3:28])=[CH:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Product: CC(O)(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.3 %

Procedure:
A 25 mL RB flask was charged with (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.200 g, 0.57 mmol) and THF (2.00 ml, 24 mmol), then cooled to 0° C. methylmagnesium bromide (0.76 ml, 2.2 mmol) was added dropwise and the mixture was stirred at room temperature for 5 hours. This was diluted with 2 N HCl (1 mL) and water (25 mL), then extracted with DCM (25 mL×2) and EtOAc (25 mL). The combined organics were washed with brine and dried with MgSO4, filtered, and concentrated. The resulting oil was purified by MPLC using a 40 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. 1-(6-phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanol (0.082 g, 39% yield) was isolated as a tan solid. MS (ESI pos. ion) m/z: 367 (MH+). Calc'd exact mass for C23H18N4O: 366.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.C(=O)(O)[O-].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCCN2CCN1CCOCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCCN2CCN1CCOCC1)c1cccs1
Reaction time: 3 h
Yield: 59.5 %

Procedure:
A solution of compound 4 (0.23 g, 0.88 mmol) in dry ethanol (20 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.502 g, 1.76 mmol) at room temperature and was stirred for 3 hours. The mixture was diluted with saturated sodium bicarbonate solution (50 mL) and was extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (20 mL) and dried (Na2SO4). The concentrated crude product was subject to flash chromatography on silica gel using 5% methanol/CH2Cl2, which resulted in a brown foam, compound 64 (0.194 g, 59%). 1H NMR (CDCl3) δ 7.66 (d, J=3.9 Hz, 1H), 7.54 (d, J=4.5 Hz, 1H), 7.06 (dd, J=3.6, 5.1 Hz, 1H), 6.53 (s, 2H), 6.46 (s, 1H), 6.21 (brs, 2H), 3.57 (t, J=9.3 Hz, 4H), 3.24 (t, J=11.4 Hz, 2H), 3.65 (t, J=12.6 Hz, 2H), 2.45-2.41 (m, 6H), 1.88-1.80 (m, 2H); MS-ESI (m/z, %): 372 (11), 371 (MH+, 100), 258 (9); ESI-HRMS calculated for C20H27N4OS (MH+): Calculated: 371.1914, Observed: 371.1900.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH3:39])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])[CH3:39]
Reactant: CCNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-ethyl-benzenesulfonamide [CAS 56445-08-0] according to general procedure II. Yellow solid. MS (ISP) 556.0 [(M+H)+]; mp 207° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]5[CH:6]=[N:7][NH:8][C:9]5=4)[N:1]=3)=[CH:25][C:24]([O:30][CH2:31][C:32]([F:35])([F:33])[F:34])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: O=C(O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 500 mg (2.61 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 20 mL of anhydrous tetrahydrofuran is added 790 mg (2.61 mmol) of 2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-2H-pyrazole-3-carboxylic acid followed by 945 μL (11.7 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 708 μL (9.1 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at 50° C. for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained (1.0 g) is engaged in the next step: LC/MS:477/479 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Reactant: CO
Agent: Cl
Product: COC(=O)C(c1ccccc1)C1CCCCC1
Yield: 99 %

Procedure:
To a stirring solution of 2-cyclohexyl-2-phenyl-acetic acid (2 g, 0.0091 mole) in methanol (100 mL) was added HCl (2 mL), and the mixture was heated at reflux for 5 hours. Methanol was removed, the residue was dissolved in ethyl acetate, and washed with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 2.2 g (99% yield) of the title compound as an oil. MS (ESI) 233.2 (M+H+).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1004 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (0.30 g, 0.16 mmol) and triethylamine (0.34 ml, 2.42 mmol) in dichloromethane (8 ml) was added p-chlorophenoxyacetyl chloride (0.36 mg, 1.77 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 80:1) to yield the title compound as a white solid (0.57 g, 100%).
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:41].[NH4+].ClCCl.C(O)C>C(O)C>[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:41])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.1 g (2.27 mmol) of 2-[N-(4-cyanophenyl)aminomethyl]benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide was stirred in 100 mL of ethanol saturated with hydrogen chloride for 5 hours, first at 0° C. and then at room temperature, until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off at a maximum bath temperature of 30° C. and the oily residue was taken up in 100 mL of absolute ethanol and mixed with 1.6 g (22 mmol) of ammonium carbonate. After 18 hours stirring at room temperature, the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water/methanol=19:1 to 4:1). When the eluates are evaporated down the desired compound is obtained as a white foam. Yield: 0.77 g (63% of theory), C27H27N5O3S (501.60); Rf value: 0.19 (silica gel; dichloromethane/ethanol=3:7); mass spectrum: (M+H)+=502.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]1[C:14]([O:16][C:17](=[O:18])[CH:8]21)=[O:15])[CH:5]=[CH2:6].[OH-].[Na+]>O>[OH:3][N:2]=[C:17]([CH:8]1[CH:9]([C:14]([OH:16])=[O:15])[CH:10]2[CH2:13][C:7]1([CH2:4][CH:5]=[CH2:6])[CH:12]=[CH:11]2)[OH:18]
Reactant: NO
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NO
Yield: 84.8 %

Procedure:
139 g (2 mol) of hydroxylamine hydrochloride are dissolved in 200 ml of water, 408 g (2 mol) of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride (prepared according to Example 1 of U.S. Pat. No. 3,105,839) are added to the solution and, with vigorous stirring, 160 g of 50% aqueous NaOH solution are then added dropwise. The mixture is subsequently heated for 1 hour under reflux, the water and traces of oily components are distilled off and the residue is taken up in toluene. The toluene phase is filtered in order to remove the sodium chloride, and the toluene is subsequently removed by rotary evaporation at 150° C. and 2000 Pa, affording 402.6 g of the product (91.5% of theory) as a pale brown viscous liquid with a viscosity of 1.28 Pa.s at 80° C.
Reaction SMILES: [OH:1][C@H:2]([C@@H:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[O:1]1[C:15]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:14][C@@H:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC2(CCCCC2)O[C@H]1C(=O)OCC
Temperature: 25 °C
Yield: 65.7 %

Procedure:
(2R,3R)-diethyl 2,3-dihydroxysuccinate (82.99 ml, 485.0 mmol) was dissolved in Toluene (400 mL) and cyclohexanone (55.29 ml, 533.5 mmol) and Amberlyst 15 ion-exchange resin (2.0 g) were added and the reaction refluxed under dean stark trap for 12 hours. The reaction was cooled to ambient temperature, filtered and concentrated. The residue was distilled at 0.5 mM Hg and the 125-140° C. fraction was collected to afford (2R,3R)-diethyl 1,4-dioxaspiro[4.5]decane-2,3-dicarboxylate (91.3 g, 66% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][S:6][C:5]1=[N:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=1.[Br:20]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Br:20][C:7]1[S:6][C:5](=[N:9][C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[N:4]([CH2:3][O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCn1ccsc1=Nc1cccc(C(=O)OC)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCn1cc(Br)sc1=Nc1cccc(C(=O)OC)n1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
6.38 g (20.6 mmol) of methyl 6-(3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridine-2-carboxylate was dissolved in 60 ml of 1,4-dioxane and 3.67 g (20.6 mmol) of N-bromosuccinimide was added thereto at room temperature. The reaction mixture was heated under reflux for 30 minutes, cooled to room temperature, diluted with 200 ml of ethyl acetate and washed with 150 ml of water for three times. After that, the reaction mixture was washed with 150 ml of brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give 7.10 g (19.8 mmol) of the title compound as a white solid.