Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:22]([C:24](/[CH:28]=[CH:29]/[C:30](=[O:32])[NH2:31])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:22]([C:24](/[CH:28]=[CH:29]/[C:30]([NH2:31])=[O:32])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1/C=C/C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn2c1/C=C/C(N)=O
Reaction time: 1 h
Yield: 25.2 %

Procedure:
247 mg Of the crude (1-{4-[3-((E)-2-carbamoyl-vinyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester were stirred in 15 mL 4M hydrogen chloride in dioxane for 22 hours at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution (pH 9). After stirring for one hour 100 mL dichloromethane were added and stirring was continued for one hour. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic extracts were washed with water and brine, dried, filtrated and the solvent was evaporated. The crude product (197.2 mg) was purified by HPLC to yield 50.3 mg of the title compound which was however contaminated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][NH:21][N:20]=2)[C:14]=1[F:30])(=[O:11])=[O:10].[H-].[Na+].Cl.[C:34]([O:37][CH2:38][CH3:39])(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][N:21]([CH:38]3[CH2:39][CH2:34][O:37]3)[N:20]=2)[C:14]=1[F:30])(=[O:10])=[O:11]
Reactant: O=S(=O)(Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1F)c1cc(F)ccc1F
Reactant: CCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cccc(-c2nn(C3CCO3)cc2-c2ccncc2)c1F)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2,5-Difluoro-N-[2-fluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide (200 mg, 0,465 mmol)(prepared as described in Example 15) in anhydrous DMF (4 mL) was added to sodium hydride (60% in mineral oil)(46 mg, 1.162 mmol, 2.5 eq) previously washed with n-hexane under argon atmosphere and cooled to 0° C. After stirring at 0° C. for 40 minutes, freshly prepared 3-oxetanol trifluoromethanesulfonyl ester (144 mg, 0.689 mmol, 1.5 eq) dissolved in dry DMF (1 mL) was added and the mixture was stirred at 0° C. for 1 h. A further addition of sodium hydride (40 mg) and 3-oxetanol trifluoro-methanesulfonyl ester (40 mg) was then made and the reaction mixture was then allowed to warm to room temperature during a night. The reaction mixture was then diluted with water and ethyl acetate. The aqueous phase was brought to pH 4-5 with HCl 2 N and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-hexane 7:3) affording 24 mg of the title product as a white solid. HPLC (254 nm): Rt: 6.99 min; 1H NMR (DMSO-d6) Shift: 10.68 (br. s., 1H), 8.52 (s, 1H), 8.36-8.40 (m, 2H), 7.51-7.59 (m, 1H), 7.31-7.49 (m, 4H), 721-7.29 (m, 1H), 7.02-7.08 (m, 2H), 5.64 (quip, J=6.9 Hz, 1H), 4.90-5.00 (m, 4H); HRMS (ESI) calcd for C23H18F3N4O3S [M+H]+ 487.1046. found 487.1043.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([N:7](CC2C=CC(OC)=CC=2OC)[S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([F:21])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([F:21])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ncc(Cl)s2)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
Methyl 4-{[(5-chloro-1,3-thiazol-2-yl)(2,4-dimethoxybenzyl)amino]sulfonyl}-2-fluorobenzoate (Preparation 31, 7.2 g, 14 mmol) was dissolved in dioxane (15 ml), 4M HCl in dioxane was added at 0° C. and the reaction mixture stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue triturated with hot MeOH (100 ml) to yield the title compound as a white solid (3.6 g, 10.2 mmol, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16]Cl)=[O:13])=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:11]([C:12]2[O:13][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=2)=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NC(C)(C)CCl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)COC(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)=N1
Yield: 62.3 %

Procedure:
A solution of 5.82 g (15 mmol) of methyl 2-chloro-3-(1-chloro-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoate and 0.81 g (20 mmol) of sodium hydroxide in 80 ml of methanol was stirred at room temperature for 8 hours. The solvent was distilled off and the residue was taken up in water and washed three times with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted three times with ethyl acetate. The organic phase was dried and the solvent was removed under reduced pressure. 3.10 g (56% of theory) of 2-chloro-3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-methylsulfonylbenzoic acid were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1)#[CH:9]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1cccc(N)c1
Product: C#Cc1cccc(NC(C)=O)c1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 30.0 g (0.256 mole) sample of 3-aminophenylacetylene was cooled at ice bath temperature and 27.0 ml (0.282 mole) of acetic anhydride was added dropwise. The ice bath was removed and the mixture stirred for 30 min. The mixture was diluted with ether and the resulting solution washed with water, NaHCO3 solution and brine. The organic phase was dried (K2CO3) and the solvent evaporated in vacuo. The crystalline residue was recrystallized from CHCl3 -hexane to give 60.7 g (89% yield) of crystalline N-(3-ethynylphenyl)acetamide, mp 94°-96° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:23]=[S:24]>C(#N)C.CCN(C(C)C)C(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:23](=[S:24])[NH:22][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:27][CH:26]=1
Reactant: NCCCCCN(Cc1ccccn1)Cc1ccccn1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=S)NCCCCCN(Cc2ccccn2)Cc2ccccn2)cc1
Yield: 19 %

Procedure:
A solution of tert-butyl 5-(bis(pyridin-2-ylmethyl)amino)pentylcarbamate (0.63 g, 1.64 mmol) in DCM (10 mL) and TFA (1.0 mL) was stirred at room temperature for 3 h. Upon completion the solvent was evaporated and the reaction mixture was diluted with DCM, washed with saturated aqueous potassium carbonate and concentrated under vacuum to afford N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine. A solution of the above product N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine, 4-isothiocyanatobenzenesulfonamide (0.35 g, 1.64 mmol) in acetonitrile (10 mL) and DIPEA (0.40 mL) was stirred at 50° C. under nitrogen for 3 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting utilizing 5% MeOH in DCM followed by 15% MeOH in DCM to give 4-(3-(5-(bis(pyridin-2-ylmethyl)amino)pentyl)thioureido) benzenesulfonamide (0.145 g, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.48 (d, 2H), 7.98 (s, 1H), 7.78-7.69 (m, 4H), 7.63 (d, 2H), 7.53 (d, 2H), 7.29-7.21 (m, 4H), 3.55 (s, 4H), 3.46-3.44 (m, 2H), 2.49-2.47 (m, 2H), 1.56-1.42 (m, 2H), 1.32-1.28 (m, 2H); ESMS m/z: 499.5 (M+H)+.
Reaction SMILES: C=O.[Na].O=[C:5]([CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C(OCC)=O.C([O-])([O-])=O.[K+].[K+]>O>[C:12]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH2:5]
Reactant: CCOC(=O)C(=O)C(C(=O)OCC)c1ccccc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
225 ml of 37 weight percent aqueous formaldehyde solution are added dropwise with stirring to a solution of 316 g of diethyl 2-oxo-3-phenylsuccinate sodium salt and 560 ml of water. During the addition, the mixture is maintained at a temperature below 25° C. The mixture is stirred for one hour at room temperature and then 152 g of anhydrous K2CO3 are added in portions over a ten minute period, while the temperature is maintained below 25° C. The resultant mixture is vigorously stirred for 1.5 hours at room temperature under a nitrogen atmosphere. The reaction mixture is diluted with 1500 ml of water and extracted with one 2.5 l. portion of ether followed by two 1.25 l portions of ether. The ether is removed and a product comprising an oil of ethyl atropate is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].[Cl-].[NH4+]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([F:1])[C:7]([Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:6]([F:8])[CH:5]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cc(F)cc(Cl)c1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 3,5-difluoro-1-chlorobenzene (10.0 g, 67 mmol) and tetramethylethlenediamine (TMEDA; 7.8 g, 67 mmol) in THF (75 mL) at −75° C., was added n-butyl lithium (2.5M, 68 mmol) and the resulting solution stirred for 30 minutes. A solution of trimethylsilyl chloride (7.6 g, 70 mmol) in THF (15 mL) was added and the solution allowed to warm to ambient temperature and stir for 25 hours. Ammonium chloride (saturated solution 15 mL) was added and the mixture extracted with ethyl ether (2×100 mL) and the combined extracts washed with brine, dried (sodium sulfate) and concentrated. The residual oil was distilled to give 1-chloro-3,5-difluoro-4-trimethylsilylbenzene (13.0 g, 60 mmol): bp 70-75° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:27]4[C:26]([NH:28][C@H:29]([C:31]5[N:36]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[C:35](=[O:43])[C:34]6=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]6[N:32]=5)[CH3:30])=[N:25][CH:24]=[N:23][C:22]=4[N:21](COCC[Si](C)(C)C)[CH:20]=3)[CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:27]4[C:26]([NH:28][C@H:29]([C:31]5[N:36]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[C:35](=[O:43])[C:34]6=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]6[N:32]=5)[CH3:30])=[N:25][CH:24]=[N:23][C:22]=4[NH:21][CH:20]=3)[CH:14]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)cc1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(NS(=O)(=O)c6ccc(O)cc6)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 79 %

Procedure:
(S)-4-Methoxy-N-(3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)benzenesulfonamide (57 mg, 0.05 mmol) was treated with boron tribromide (1M in dichloromethane, 536 μL, 0.54 mmol) in dichloromethane (1.15 mL) and then with a solution of ammonia (7N in methanol, 1.15 ml, 6.05 mmol) according to the method described in Example 27. The residue was purified using SP1 ® Purification System (0% to 6% dichloromethane-2-propanol) to obtain 25 mg (72% yield) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[C:15]([O:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+]>S(Cl)(Cl)=O.C(OCC)C.O>[C:15]([O:19][NH:20][C:9](=[O:11])[CH2:8][CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)CCOc1ccc(I)cc1
Reactant: CC(C)(C)ON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)ONC(=O)CCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of 3-(4-iodophenoxy)propanoic acid (1.00 g, 3.42 mmol) in thionyl chloride (6.0 mL) was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl ether, and concentrated in vacuo. The residue was azeotroped three times with ethyl ether, dried under high vacuum, and taken up in dichloromethane (7 mL) under N2. To the solution was added a solution in dichloromethane of O-tert-butylhydroxylamine (8.60 mmol; prepared by dissolving O-tert-butylhydroxylamine hydrochloride in water, making the free base with aqueous 10% Na2CO3, and extracting the solution with dichloromethane, and drying the organic solution over MgSO4), and the reaction mixture was stirred for two hours. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil which crystallized on standing to give O-tert-butyl 3-(4-iodophenoxy)propanohydroxamic acid (1.22 g, 98%).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1(C)C=CC=CC=1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]2[NH:27][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:28][CH:29]=1)([O-:21])=[O:20]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccncc1
Yield: 15.9 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.0 g) and 4-nitrobenzylamine (2.2 g) were dissolved in toluene (40 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(4-nitrophenyl)-5-(4-pyridyl)imidazole-4-carboxylate (0.7 g), melting point not less than 280° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:26])([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:5][C:4]=1[NH2:27].[C:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH2:37][C:38](O)=O)=[CH:32][CH:31]=1)#[N:29].C(N1C=CN=C1)(N1C=CN=C1)=O>C(O)(=O)C>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH2:37][C:38]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:10]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)=[O:11])[CH3:26])=[CH:5][C:4]=3[N:27]=2)=[CH:34][CH:35]=1)#[N:29]
Reactant: CNc1ccc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N2CCCC2)cc1N
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N3CCCC3)ccc21

Procedure:
Prepared analogously to Example 1g/h from 2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(tert.butyloxycarbonylamino)-1-pyrrolidino-propan-1-one, 4-cyano-phenylglycine/carbonyldiimidazole and subsequent treatment with glacial acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:33]=3)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1cccc(B(O)O)c1
Product: CC(C)c1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)cs2)c1
Yield: 44.9 %

Procedure:
2-Chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropyl phenyl boronic acid (42 mg, 0.26 mmol) to give the title compound (28 mg, 45%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [S:1]1[C:5]([CH:6]([O:11][CH3:12])[C:7](OC)=[O:8])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.O.[NH2:18][NH2:19]>C(O)C>[S:1]1[C:5]([CH:6]([O:11][CH3:12])[C:7]([NH:18][NH2:19])=[O:8])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: NN
Reactant: COC(=O)C(OC)c1cc2ccccc2s1
Solvent: CCO
Solvent: O
Product: COC(C(=O)NN)c1cc2ccccc2s1
Temperature: 50 °C
Yield: 104.1 %

Procedure:
To a solution of methyl 2-(benzo[b]thiophen-2-yl)-2-methoxyacetate (0.174 g, 0.74 mmol) in absolute ethanol (3 mL) was added hydrazine hydrate (0.14 mL, 2.87 mmol) and the mixture was heated at 50° C. for 20 hours. After cooling to room temperature, the solution was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 2-(benzo[b]thiophen-2-yl)-2-methoxyacetohydrazide as a colorless oil (0.182 g, quantitative yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[C@H:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][C@H:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN[C@H](C)C1
Reaction time: 12 h

Procedure:
A suspension of 3.0 g (R)-2-Methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester and 0.4 g Pd/C (10%) in 48 ml ethyl acetate was stirred under an atmosphere of hydrogen (3 bar) for 12 h. The mixture was filtrated over a plug of Celite, washed with ethyl acetate and the combined wash solutions concentrated to give the title compound as colourless oil. Yield: 1.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:6]P(=O)(OCC)OCC.[CH3:22][C:23]([CH3:25])=O.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:23]([CH3:25])[CH3:22])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)c(OC)c1)OCC
Reactant: CC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of diethyl (3-methoxy-4-methoxycarbonylbenzyl)phosphonate (1.28 g) and acetone (1.5 ml) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride-oil dispersion (162 mg). The reaction mixture was stirred at room temperature for 14 hours and then poured into ice-cooled 10% citric acid. The mixture was extracted with ether and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (85:15) to give methyl 2-methoxy-4-(2-methyl-1propenyl)benzoate (184 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]([CH3:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[CH3:38][N:27]([CH3:26])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Product: CN(C)c1ccc(CC(=O)Nc2cccc(-c3n[nH]c4ccc(C(N)=O)cc34)c2)cc1
Yield: 14.3 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(dimethylamino)phenylacetic acid (0.13 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 33 mg (13% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.15 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.35 (br s, 1H), 7.18 (m, 2H), 6.68 (d, 2H), 3.5 (s, 2H), 2.9 (s, 6H); ES-MS (m/z) 414 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(Cl)Cl.C(#N)C>[O:33]1[CH2:34][CH2:35][N:30]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:31][CH2:32]1
Reactant: N#Cc1cccc(O)c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cccc(N2CCOCC2)c1
Temperature: -10 °C
Yield: 26.4 %

Procedure:
3-Cyanophenol (1.77 g, 14.9mmol) and triethylamine (6.30 ml, 45.2 mmol) were dissolved in methylene chloride (75 ml) and stirred at -10° C. in an argon gas atmosphere. A solution of trifluoroacetic anhydride (3.79 ml, 22.5 mmol) dissolved in methylene chloride (15 ml) was added dropwise thereto, and after the addition was completed, the mixture was stirred for 1.5 hours. After the reaction was completed, the solvent was removed under reduced pressure, and an aqueous solution of sodium hydrogen carbonate was added to the resulting concentrated residue and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated. The resulting concentrated residue was purified by silica gel column chromatography (chloroform/methanol=100) to give oily substances. The resulting oily substances were dissolved in acetonitrile (40 ml). Morpholine (33.0 ml, 378 mmol) was added thereto and the mixture was stirred for 3 days under heating at reflux. The solvent and unreacted reagents were distilled off under reduced pressure, water was added to the concentrated residue, and the mixture was extracted with chloroform. The organic layer was dried (over sodium sulfate), the drying agent was filtered off, and the filtrate was concentrated. The resulting concentrated filtrate was purified by silica gel column chromatography (eluent: chloroform/hexane=1/2) to give the title compound (0.74 g, 26%) as oily substances.