Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21]S(C4C=CC(C)=CC=4)(=O)=O)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1.O[CH2:33][C:34]1[N:38]=[CH:37][N:36]([CH3:39])[N:35]=1>>[CH3:1][O:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:33][C:34]4[N:38]=[CH:37][N:36]([CH3:39])[N:35]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1
Reactant: COc1cc(-c2nnc3c4ccccc4c(OS(=O)(=O)c4ccc(C)cc4)nn23)no1
Reactant: Cn1cnc(CO)n1
Product: COc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C)n4)nn23)no1

Procedure:
The title-compound was prepared from 3-(5-methoxyisoxazol-3-yl)-6-(4-toluenesulphonyloxy)-1,2,4-triazolo[3,4-a]phthalazine (prepared as described in Example 118 part a) and 3-hydroxymethyl-1-methyl-1,2,4-triazole (prepared using the conditions of Itoh and Okongi, EP-A-421210) using the conditions given for in Example 98, 1H NMR (360 MHz, CDCl3) δ 3.96 (3H, s, CH3), 4.15 (3H, s, CH3), 5.72 (2H, s, CH2), 6.30 (1H, s, Ar—H), 7.79 (1H, m, Ar—H), 7.95 (1H, m, Ar—H), 8.07 (1H, s, Ar—H), 8.28 (1H, d, J=8.4 Hz, Ar—H), 8.68 (1H, d, J=8.4 Hz, Ar—H); MS (ES30) m/e 379 [MH]+; Anal. Found. C, 53.97; H, 3.73; N, 29.62. C17H14N8O3 requires C, 54.04; H, 3.48; N, 29.32%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)[CH:7]=1.O.[NH2:17][NH2:18]>O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:18][N:17]=[C:8]2[C:10]1[NH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NN
Reactant: O=C(c1ccc[nH]1)c1cc(Br)ccc1F
Solvent: O
Product: Brc1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Temperature: 150 °C
Yield: 99 %

Procedure:
A slurry containing (5-bromo-2-fluoro-phenyl)-(1H-pyrrol-2-yl)-methanone (Preparation #16b, 2.40 g, 8.96 mmol) and hydrazine hydrate (35 mL) was sealed and heated by microwave iat about 150° C. for about 1 hour. The reaction was cooled to ambient temperature and diluted with water (150 mL). The product was extracted with EtOAc (150 mL), washed with 2N HCl solution (50 mL), saturated NaHCO3 solution (50 mL) and finally a saturated NaCl solution. The EtOAc layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield 5-bromo-3-(1H-pyrrol-2-yl)-1H-indazole (2.38 g, 99%) as an oil. RP HPLC (Table 1, Method e) Rt=2.95; m/z: (MH)+ 262/264
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:11].[SH:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:11]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1nc(C)ccc1NC(=O)CCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(C)ccc1NC(=O)CCCCCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a DMF (1.5 ml) solution of this amide (131 mg, 0.35 mmol) and 2-mercaptobenzoxazole (58 mg, 0.385 mmol) were added 18-crown-6 (9 mg, 0.035 mmol) and potassium carbonate (58 mg, 0.42 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 30 g, eluent—hexane:ethyl acetate=4:1→3:1) to obtain 123 mg (yield 79%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18]>CN(C=O)C.O>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=[O:10])[N:9]([CH2:18][CH:17]=[CH2:16])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)oc(=O)c2ccc(F)cc21
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of 7-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (5.01 g, 27.7 mmol) in DMF (100 ml) at 0° C. was added sodium hydride (1.11 g, 27.7 mmol, 60% in paraffin) over 15 min. Allyl iodide (2.6 ml, 27.7 mmol) was added and the solution stirred for 2 h, then poured onto ice (100 g) in water (200 ml). The precipitate was collected, washed with water, then hexane and dried under vacuum at 40° C. to yield the title compound (4.53 g, 74%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[N:17]=[C:16]([C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=1)[CH3:11].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([C:18](=[N:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:21]([CH3:23])[CH3:22])[CH3:19])[N:17]=1)[CH3:11]
Reactant: CC(C)c1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-{6-[1-(2,6-Dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 (5.0 g, 0.0188 mol), 3.30 g (0.0244 mol) of 2-isopropyl-phenylamine 9, 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under a flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 20 ml of ethanol. The yield of (2,6-dimethyl-phenyl)-(1-{6-[1-(2-isopropyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-amine 8 was 4.90 g (68%) as a yellow solid.
Reaction SMILES: IC.[F:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.N12CCCN=C1CCCC[CH2:18]2>CN(C=O)C.C(OCC)(=O)C>[F:3][C:4]1[C:9]2[N:10]([CH3:18])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21
Temperature: 65 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Iodomethane (0.393 ml, 6.31 mmol) is added in portions to crude 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (Step 5, 1.00 g, 5.05 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.94 ml, 6.31 mmol) in DMF (10 ml). The reaction is stirred at 65° C. overnight, diluted with ethyl acetate, washed with 2N HCl and saline, dried (MgSO4), and evaporated to give crude product containing trace amounts of undesired 5-nitro isomer. Purification by flash column chromatography (20% ethyl acetate/hexane) gives pure product as a white solid (0.89 g, 83%); mp 118-9° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[CH2:5][CH:6]([NH:20][CH3:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:22])[CH2:5][CH:6]([N:20]([C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:25]([C:24]([F:23])([F:38])[F:39])[CH:26]=1)[CH3:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC(CC(=O)OC)C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 6.8 g (21 mmol) of 3-methylamino-4,4-diphenyl-butanoic acid methyl ester hydrochloride in 100 ml of methylene chloride is added to a solution of 4.2 ml (22 mmol) of 3,5-bistrifluoromethyl-benzoyl chloride in 100 ml of methylene chloride. Then, at 0° C., 6.6 ml (46 mmol) of triethylamine and 0.26 g (2.1 mmol) of 4-dimethylaminopyridine are added. After 6 hours the reaction mixture is diluted with ethyl acetate and washed twice with water and once with brine. The organic phase is dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride/methanol (99:1 to 95:5). The title compound is obtained in the form of a light-yellow solid. TLC: methylene chloride/methanol (95:5) Rf =0.88; Rt (HPLC)=21.4 min; 1H-NMR (400 MHz, d6 -DMSO, 150° C.) d 7.97 (br, 1H), 7.45-7.19 (m, 12H), 5.46 (br, 1H), 4.46 (d, 1H), 3.54 (s, 3H), 2.87 (dd, 1H), 2.72 (s, 3H), 2.47 (dd, 1H); FAB-MS (M+H)+ =524.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[NH:12][CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(F)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1nc2cc[nH]c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (2742 mg, 7.85 mmol) in MeOH (20 mL) and water (20 mL) was added NaOH (628 mg 15.7 mmol). The mixture was stirred at RT for 1 h. The reaction mixture was quenched by adding a sat'd aq. NH4Cl and extracted with EtOAc. The extract was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a petroleum ether:EtOAc gradient (10:1-0:1) to afford 758 mg (60%) of 6-fluoro-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile. MS (ESI): m/z=162.3 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:8]=[C:7]1[CH:6]=[CH:5][O:4][CH:3]=[C:2]1[O:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=c1ccocc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1coccc1=O
Reaction time: 1.25 h

Procedure:
A mixture of 3-hydroxy-4H-pyran-4-one (1.12 g), ethyl 2-bromoacetate (1.7 g) and potassium carbonate (1.4 g) in ethanol (30 ml) was stirred at 67° to 70° C. for 75 minutes. The reaction mixture was allowed to stand at room temperature. An insoluble substance was filtered off, and the filtrate was adjusted to pH 4 to 5 with conc. hydrochloric acid and the ethanol was removed. To the residue was added ethyl acetate, and the resultant mixture was washed with an aqueous solution saturated with sodium chloride and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on silica gel (15 g) with an eluent (ethyl acetate:benzene=1:5) to give crystals of ethyl 2-(4-oxo-4H-pyran-3-yloxy)acetate, mp 58° to 60° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][C@@H:10]1[OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:28]OS(OC)(=O)=O.O>C1COCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][C@H:10]1[O:25][CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NC(=O)OC(C)(C)C

Procedure:
benzyl (3S,4S)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate (5.00 g) is dissolved in THF (6 mL) and combined with 30 mL aqueous, semiconcentrated NaOH solution, benzyltriethylammonium chloride as well as dimethylsulphate (2.26 mL). After 22 h H2O (200 mL) is added and the mixture is extracted with EtOAc (150 mL). The organic phase is dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. Purification is carried out using a silica gel column (cHex/EtOAc 65/35).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].CN(C=O)C>O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:36][N:35]=[N:34][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2
Reactant: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC#N)ccc3c2)cnn1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)cnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
A mixture of 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.15 g, 0.3 mmol), prepared in the previous step, sodium azide (0.059 g, 0.9 mmol), ammonium chloride (0.048 g, 0.9 mmol) and 10 mL of DMF was stirred at 100° C. for 1.5 h. By TLC starting material remained. Additional sodium azide (0.059 g, 0.9 mmol) and ammonium chloride (0.048 g, 0.9 mmol) were added and the reaction stirred at 100° C. for 2 h. Again by TLC starting material remained. Additional sodium azide (0.059 g, 0.9 mmol) and ammonium chloride (0.048 g, 0.9 mmol) were added and the reaction stirred at 100° C. for 5 h. The reaction was diluted with water and extracted four times with ethyl acetate. The organic layers were combined and acidified with ˜3 mL 1N HCl. The mixture was swirled for one minute and then the solution was dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting residue was taken up in 20 mL of water. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (0.107 g, 65%) as a tan solid, mp 219-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([C:17](=O)[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.CC([O-])=O.[Na+].Cl.[NH2:28][OH:29]>CO>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([C:17](=[N:28][OH:29])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cnc3cc(C(C)=O)ncc32)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2cnc3cc(C(C)=NO)ncc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a mixture of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanone (500 mg, 1.78 mmol) and NaOAc (1.21 g, 17.80 mmol) in MeOH (10 mL) at RT was added hydroxylamine hydrochloride (618 mg, 8.90 mmol). The reaction was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. To the residue was added water (100 mL) followed by extraction with EtOAc (50 mL×3). The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford 320 mg (61%) of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanone oxime as a yellow solid. MS (ESI): m/z=297.2 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:19]([NH:20][C:21]([SH:23])=[NH:22])=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2].Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:19]([NH:20][C:21]3[S:23][CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=3)=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2]
Reactant: N#Cc1cc2c(NC(=N)S)n[nH]c2nc1-c1ccc(O)cc1F
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2n[nH]c3nc(-c4ccc(O)cc4F)c(C#N)cc23)n1
Yield: 44.8 %

Procedure:
To 66 mg (0.20 mmol) of N-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)carbamimidothioic acid diluted in 2 ml of ethanol are added 57 mg (0.20 mmol, 68%) of ethyl 3-bromo-2-oxopropanoate. The solution is refluxed for 2 h. The solid is filtered, washed with ethanol and dried to give 38 mg of ethyl 2-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-ylamino)thiazole-4-carboxylate in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH:23]C(=O)C(F)(F)F)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(CNc1cc(Cl)cc(Cl)c1)N1Cc2ccccc2C(NC(=O)C(F)(F)F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC1CN(C(=O)CNc2cc(Cl)cc(Cl)c2)Cc2ccccc21
Yield: 34.3 %

Procedure:
To a mixture of N-(2-(2-(3,5-dichlorophenylamino)acetyl)-1,2,3,4-tetrahydroisoquinolin-4-yl)-2,2,2-trifluoroacetamide (0.45 g, 1.0 mmol), in aq. MeOH (15 mL) was added K2CO3 (1.0 g, 6.0 mmol) and the reaction mixture was heated to reflux for 2.5 h. The reaction mixture was concentrated in vacuo to give a residue which was purified by column chromatography (silica gel, gradient MeOH in DCM) to give (0.120 g, 35%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 7.30-7.19 (m, 3H), 7.05-6.95 (m, 1H), 9.71 (s, 1H), 6.45 (d, 2H, J=11.2 Hz), 5.19 (d, J=8.0 Hz, 1H), 4.65 (s, 1H), 4.89-3.99 (m, 2H), 3.85-3.69 (m, 3H), 3.3-3.2 (m, 2H). LCMS: M/z: (M+1):350
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>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>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:26]([O-:28])=[O:27])[CH:34]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: O=[N+]([O-])c1cccc(B(O)O)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: Cc1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc([N+](=O)[O-])c2)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.4 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 120 mg of 3-nitrobenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to afford 100 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-(3-nitrophenyl)-3(2H)-furanone as a solid. mp: 158-159° C. NMR: δ1.61 (s, 6H), 3.09 (s, 3H), 7.57 (t, J=7.8 Hz, 1H), 7.64 (m, 1 H), 7.81 (d, J=9.0 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.19 (m, 2H). IR (cm−1): 2982, 1697, 1529, 1403, 1349, 1150, 959, 770.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([O:27]C)=[O:26])[C:12](=[O:29])[C@H:11]1[CH2:30][CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>O.C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([OH:27])=[O:26])[C:12](=[O:29])[C@H:11]1[CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CN1C(=O)[C@@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@H]1CC1CCCCCC1

Procedure:
24 mg (1.3 mmol) lithium hydroxide in 1.0 ml of water were added to 0.55 g (1.1 mmol) (2R)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate (isomer 4.1.1) in 5 ml THF. After 2 h at RT the mixture was neutralised with 0.1 M hydrochloric acid solution. The reaction mixture was evaporated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:34]1([NH:40][NH2:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21]/[C:22](/[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[N:41]\[NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC/C(=N\Nc3ccccc3)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure E and Scheme AX using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and phenylhydrazine: ESMS m/e: 542.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:4]2[C:5](OC(=O)[NH:9][C:3]=12)=[O:6].O.[NH3:16]>CN(C=O)C.O>[NH2:9][C:3]1[C:2]([CH3:1])=[C:13]([Cl:14])[CH:12]=[CH:11][C:4]=1[C:5]([NH2:16])=[O:6]
Reactant: N
Reactant: Cc1c(Cl)ccc2c(=O)oc(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)ccc(C(N)=O)c1N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Using two inlets, at 80° C. a suspension of 4.64 g (0.0219 mol) of 3-methyl-4-chloroisatoic anhydride in 21 ml of DMF and 3.1 g (0.0219 mol) of 25% strength ammonia water in 6 ml of water were added simultaneously with stirring and over a period of 15 min to 8 ml of water. The mixture was stirred at 80° C. for 1 h and then cooled and extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, giving 2.61 g (64.4% of theory) of the title compound as colorless crystals of m.p. 206-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:13].[BH4-].[Na+].O.[ClH:23]>CCO>[ClH:23].[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:14]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1)[OH:13]
Reactant: COc1cccc(CC(=O)c2ccncc2)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CC(O)c2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(2,3-dimethoxyphenyl)-1-(4-pyridinyl)ethanone (2.4 g, 0.009 mol) in EtOH (25 ml) was added, portionwise, NaBH4 (0.005 mol). The reaction was stirred at ambient temperature for 2 h, and then it was poured into water. The aqueous solution was extracted with EtOAc, and the extract was washed (water), dried (magnesium sulfate) and concentrated to afford an oil. The oil was triturated with Et2O and 1.9 g of a white solid resulted. The solid was dissolved in EtOH and ethereal HCl was added to precipitate a white hydrochloride salt. The salt was recrystallized twice from EtOH to afford the alcohol as a white solid mp 204-206° C.