Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][CH2:30][C@@H:31]([CH3:33])[N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][CH:15]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:33][C@@H:31]1[CH2:30][O:29][C:28]([C:25]2[NH:24][C:23]([C:21]3[CH:22]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=4)[CH:20]=3)[O:5][C@@H:4]([CH3:34])[CH2:3][OH:2])=[CH:27][CH:26]=2)=[N:32]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)=N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine (1.20 g, 2.47 mmol) synthesized in Example (84b) was dissolved in methylene chloride (25 mL), followed by cooling to −78° C., and boron tribromide (1.0 mol/L methylene chloride solution, 2.72 mL, 2.72 mmol) was added under nitrogen atmosphere. After the temperature was raised naturally and stirring was carried out at room temperature for 30 minutes, a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired compound (895 mg, 77%) as a white solid.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([N:17]2[C:21]([NH2:22])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH:8]=1)C.[NH3:28].CO>>[NH2:22][C:21]1[N:17]([C:9]2[CH:8]=[C:7]([CH2:6][C:5]([NH2:28])=[O:4])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:18]=[C:19]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:20]=1
Reactant: N
Reactant: CCOC(=O)Cc1cc(-n2nc(C(C)(C)C)cc2N)cc2ccccc12
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(N)n(-c2cc(CC(N)=O)c3ccccc3c2)n1
Yield: 41 %

Procedure:
[3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]acetic acid ethyl ester hydrochloride (see WO 2006/071940, 1.60 g, 4.55 mmol) was treated with ammonia in methanol (7 M, 13 mL, 91 mmol) and the reaction mixture was heated in a sealed tube for 6 days. The solvent was removed in vacuo and the residue was chromatographed to provide 2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)naphthalen-1-yl)acetamide (610 mg, 41% yield). MS (ESI) m/z: 323.3 (M+H+).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:34])[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][C:30]1[N:34]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:26][N:29]=1
Reactant: NC(CCO)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: O=C(N1CCSCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CCO)no2)C1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 201 mg (1.938 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 494 mg (68% of theory)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[F-].[Cs+].Cl[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:17][N:18]2[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:14][CH:13]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:1]1[CH:5]=[CH:4][C:3]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:17][N:18]3[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])=[CH:14][CH:13]=2)=[CH:2]1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: OB(O)c1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccsc3)ccc12
Temperature: 100 °C
Yield: 50.5 %

Procedure:
522 mg of 3-thienylboronic acid, 1.24 g of caesium fluoride, 13 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 25, in 30 cm3 of dioxane. The mixture is then heated at about 100° C. for 2 hours. 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl and 13 mg of palladium acetate are added and the mixture is refluxed for 17 hours. The mixture is then allowed to return to about 19° C. and then filtered through a sinter funnel, and 75 cm3 of ethyl acetate and 50 cm3 of distilled water are added. The insoluble material is filtered off on a sinter funnel. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume) and collecting 50 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 570 mg of N-[6-(3-thiophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]I)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1>C1COCC1.[Zn]>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:20]([CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1
Reactant: COc1ccc(CCCI)cc1OC
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1ccc(CCCc2nc(Cl)nc(N3CCOCC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-propyl iodide (1.224 g, 4.00 mmol, 1.00 equiv.) in 20 mL dry THF was added highly active zinc (suspension in THF, Rieke metal from Aldrich, 5.2 mL 0.05 g/mL, 4.00 mmol, 1.00 equiv.). The mixture was stirred at room temperature overnight. 2,4-dichloro-6-morpholin-4-yl-1,3,5-triazine (0.936 g, 4.0 mmol, 1.00 equiv.) and trans-benzyl-(chloro)-bis-(triphenylphosphine)palladium(II) (0.03 g, 0.04 mmol, 0.01 equiv.) were added, and the reaction mixture was stirred at room temperature for 8 hours. Usual workup and flash chromatography purification gave 4-chloro-2-[3-(3, 4-dimethoxyphenyl)propyl]-6-morpholin-4-yl-1,3,5-triazine as a light yellow solid which was treated with hydrazine following the typical procedure to yield {4-[3-(3,4-Dimethoxy-phenyl)-propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-hydrazine as a white solid (0.85 g, 2.27 mmol, 57%). MS (ESI): m/z 375.2 (M+H)+.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:20][CH:19]=1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Reactant: CSc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NN=C(Sc2ccc(SC)cc2)C(C)=O)cc1

Procedure:
A suspension of 31.7 g (0.139 mol)of 1-chloro-1-[(4-methoxyphenyl)hydrazono]-2-propanone in 400 ml of ethanol was treated with 23.4 g of 4-methylthiothiophenol and 23.4 of triethylamine. The suspension was heated at reflux for 2 hours and cooled. The resultant suspension was filtered and the precipitate was washed with 1 portion of cold ethanol. The solids were dried in vacuo to yield 1-[(4-methylthiophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 124-127° C. 1H NMR(400 MHz, CDCl3): 2.41 (s, 3 H), 2.54 (s, 3 H), 3.78 (s, 3 H), 6.87 (d, J=8.8 Hz, 2 H), 7.12 (m, 6 H), 9.20 (broad s, 1 H).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:8]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=1.[F:35][C:36]1[N:41]=[C:40]([F:42])[C:39]([F:43])=[C:38](F)[C:37]=1[F:45]>CCCCC.O1CCCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:9]2[NH:10][CH:11]=[C:7]([C:38]3[C:37]([F:45])=[C:36]([F:35])[N:41]=[C:40]([F:42])[C:39]=3[F:43])[C:8]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[CH:27][CH:26]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2[nH]cc(-c3c(F)c(F)nc(F)c3F)c2-c2ccncc2)cc1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
1.8 ml (2.75 mmol) of 1.54 N solution of t-butyllithium in pentane were added to a solution of 650 mg (1.37 mmol) of 4-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in step 7(iii) above] in 15 ml of tetrahydrofuran at −78° C. and the mixture was stirred for 10 minutes. At the end of this time, 165 μl (1.51 mmol) of pentafluoropyridine were added to the reaction mixture. The cooling bath was then removed and the mixture was stirred for 30 minutes. At the end of this time, 70 ml of water and 50 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, and then this was extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 4:1 by volume mixture of hexane and ethyl acetate as the eluant to give 346 mg (yield 65%) of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[O:8][C:7]=1[CH3:14])=[O:5])[CH3:2].S(N)(=O)(=O)[OH:16].Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:11][C:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[O:8][C:9]=1[C:12]([OH:16])=[O:13]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)c1c(C)oc(C=O)c1C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)oc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4-Dimethyl-5-formylfuran-3-carboxylic acid ethyl ester (1.78 g, 9.1 mmol) reported in the references was dissolved in a mixture of acetic acid (32 ml) and water (8 ml). Amidosulfuric acid (1.19 g, 12.2 mmol) was added to the solution, and cooled to 0° C. in an ice bath. Sodium chlorite was added and stirred for 2 hours, and after addition of water to reaction mixture, precipitate was collected by filtration, thereby giving 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (1.01 g, 52%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O-:14].[Na+]>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:14][CH3:13])=[N:7]2
Reactant: C[O-]
Reactant: Clc1ccc2c(Br)cccc2n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(Br)cccc2n1
Temperature: 25 °C

Procedure:
To a suspension of 5-bromo-2-chloroquinoline (2.81 g, 11.6 mmol) in MeOH (25 mL) was added sodium methoxide (30% w/w in MeOH, 10.4 mL, 54.7 mmol). The mixture was refluxed for 3 hours, allowed to cool to room temperature, diluted with water, then extracted with EtOAc. The combined extracts were washed with water then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.36 (d, J=9.1 Hz, 1H); 7.81 (d, J=8.4 Hz, 1H); 7.63 (dd, J=7.6, 1.1 Hz, 1H); 7.46 (t, 1H, J=7.9 Hz); 6.98 (d, J=9.1 Hz, 1H); 4.08 (s, 3H); LC1 1.85 min. (M+H) 238.
Reaction SMILES: [OH:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C1CCC(N=C=NC2CCCCC2)CC1.C1C=NC2N(O)N=NC=2C=1.[CH3:34][C:35]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>CN(C=O)C>[OH:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([N:48]1[CH2:49][CH2:50][N:45]([C:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[C:35]([CH3:34])[CH:44]=2)[CH2:46][CH2:47]1)=[O:7]
Reactant: CC(O)/C=C/C(=O)O
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(C(=O)/C=C/C(C)O)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4-Hydroxypent-2-enoic acid (67 mg, 0.52 mmol) was dissolved in anhydrous DMF (2.5 ml), DCC (107.5, 0.52 mmol) and HOAt (106.7 mg, 0.79 mmol) were added and the mixture was stirred at room temperature for 15 minutes. 2-Methyl-4-piperazin-1-yl-quinoline (118.2 mg, 0.52 mmol) was added and stirring was continued for 90 minutes. The mixture was evaporated to dryness, taken up in a mixture of acetonitrile and methanol and filtered. The filtrate was evaporated to dryness again and purified by preparative HPLC (gradient of water containing 0.1% TFA and acetonitrile). 110 mg were obtained (0.33 mmol, 65%). MS (ES): m/z=326.1 [M+1]+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Br.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>CCOCC>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:3]1[CH:2]=[C:1]([CH3:9])[CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccccc1Br
Reactant: Cc1ccccc1[Mg]Br
Solvent: CCOCC
Product: Cc1cccc(-c2ccccc2F)c1
Temperature: 25 °C

Procedure:
A 1.46M solution (45 ml) of toluylmagnesium bromide in ether was added to a mixture of 10 g 2-bromofluorobenzene and 250 mg bis(diphenylphosphinoethane)-nickel dichloride in 70 ml dry diethyl ether. The mixture was then heated at reflux for 18 hours. The mixture was cooled to room temperature and quenched with 10% aqueous ammonium chloride, followed by 1M hydrochloric acid, and then partitioned between ether and water. The aqueous phase was extracted once more with ether and the combined organic extracts were dried and evaporated yielding the crude product as an oil which was purified by elution from silica gel with hexanes. The product was a colorless oil (7.0 g, 66% yield) which was used without further purification. NMR (CDCl3, 60MHz): 7.4-6.9 (m, 8H), 2.4 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].O.Cl.[O:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=O)[CH2:12][CH2:11]1>C(O)C>[O:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[N:1][N:2]2[CH2:6][CH2:5][O:4][C:3]2=[O:7])[CH2:12][CH2:11]1
Reactant: NN1CCOC1=O
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1OCCN1N=C1CCOc2ccccc21

Procedure:
A 62 g (0.61 mole) portion of 3-amino-2-oxazolidinone was charged in a 500 ml, 3-necked flask equipped with a thermometer, stirrer and reflux condenser, and treated successively with 92 ml of H2O, 8 ml of 10% HCl and 42 g (0.28 mole) of 4-chromanone in 200 ml of ethanol. The reaction mixture was refluxed for 36 hrs., stripped in vacuo to one-half volume and cooled in the refrigerator overnight. The slurry was filtered and the white crystalline solid washed with 50 ml of isopropanol then 200 ml of ether and dried; m.p. 105°-108°. Yield: 44 g (68%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:3]=1.[F:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:3][C:2]([C:36]2[CH:37]=[N:38][C:33]([F:32])=[CH:34][CH:35]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(Cl)cc1-c1cccnc1
Reactant: OB(O)c1ccc(F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccc(F)nc2)cc1-c1cccnc1
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
10 mg (0.02 mmol) of 4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.5 mg (0.03 mmol) of (6-fluoropyridin-3-yl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 3 mg (27% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19]C(C)(C)C)=O)[CH2:13][CH2:12]2)[C:5]([Br:24])=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[C:41]1([N:47]=C=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:47][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:19])[CH2:15][CH2:16]2)[C:5]([Br:24])=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(C(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A solution of tert-butyl 4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazine-1-carboxylate (250 mg, 0.62 mmol) in CH2Cl2 (2.5 mL) at 0° C. was treated with TFA (2.5 mL) and stirred at 0° C. for 1.5 h. After this time, the solvents were evaporated in vacuo and the excess TFA removed by azeotroping with toluene (3×10 ml). The residue was suspended in CHCl3 (2.5 mL) and treated with DIPEA (5 eq, 3.11 mmol, 0.54 mL) and phenyl isocyanate (1.05 eq, 0.65 mmol, 0.07 mL). The reaction was warmed to room temperature and stirred for 12 h. The formed precipitate was filtered off and dried to give the product as a yellow solid (221 mg, 84% for two steps); 1H-NMR (500 MHz, DMSO-d6) 3.07 (br s, 4H, piperazine N(CH2)2), 3.58 (br s, 4H, piperazine N(CH2)2), 6.94 (tt, J=7.4, 1.1 Hz, 1H, phenyl H-4), 7.03 (br s, 2H, NH2), 7.24 (dd, J=8.5, 7.5 Hz, 2H, phenyl H-3 & H-5), 7.45 (dd, J=8.5, 1.1 Hz, 2H, phenyl H-2 & H-6), 8.21 (s, 1H, pyridine H-6), 8.59 (br s, 1H, NH);
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]([NH2:28])=O)[N:23]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]#[N:28])[N:23]=1
Reactant: COc1ccc(CNc2nc(CCC(N)=O)nc3sc4c(c23)CCCC4)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(CNc2nc(CCC#N)nc3sc4c(c23)CCCC4)cc1Cl
Reaction time: 1 h

Procedure:
1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0°. 1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionamide is then added. The mixture is stirred for one hour. After customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]-benzothieno[2,3-d]pyrimidine-2-yl]propionitrile is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28].[CH2:29]([N:36]1[C:40]2=C(N3CCC4C(=CC=CC=4)C3)N=CC=C2C=[C:37]1C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[ClH:28].[CH2:1]([N:8]1[C:12]2=[C:13]([N:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[N:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:29][N:36]([CH3:40])[CH3:37])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2ccnc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(CN(C)C)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Yield: 72 %

Procedure:
In accordance with the same procedures as in Example 619, except for using 2-(1-benzyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline obtained by treating the compound prepared in Example 614 with a saturated sodium bicarbonate solution, the titled compound was obtained as a white solid. (Yield: 72%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:20]12[NH:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][O:22][CH2:21]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:27]3[CH:20]4[CH2:26][CH2:25][CH:24]3[CH2:23][O:22][CH2:21]4)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CC2COCC1N2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3C4CCC3COC4)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. Yellow solidl. MS (m/e): 367.1 ([{37Cl}M+H]+, 35%), 365.1 ([{35Cl}M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][C:6](=[O:14])[C:5]2([CH3:16])[CH3:15].N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:15][C:5]1([CH3:16])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH:3]=2)[NH:7][C:6]1=[O:14]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)C(=O)Nc2cc([N+](=O)[O-])c(N)cc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of C1 (3.1 g) and dry pyridine (3.5 ml; 42 mmol) in dry CH2Cl2 (75 ml) is added 4-methoxy-benzoyl chloride (2.63 g; 15.4 mmol) over a period of 2 min. After addition the mixture is stirred at RT for 20 h. CHCl3 (200 ml) is added and the organic layer is washed with sodium hydroxide solution (0.5 N) and water, dried over MgSO4 and concentrated in vacuo. The crude material is triturated with boiling EtOH and the precipitate is collected by filtration (3.73 g).