Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:17][C:18]([C:20]1[O:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH:21]=1)=[O:19].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].C([O:40][CH2:41][CH3:42])(=O)C>>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[CH3:17][C:18]([C:20]1[O:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([O:33][CH2:32][C@@H:41]([OH:40])[CH2:42][N:14]3[CH2:15][CH2:16][CH:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH2:12][CH2:13]3)[C:22]=2[CH:21]=1)=[O:19]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)/C=C\C(=O)O
Product: CC(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1

Procedure:
By the reactions in the same manner as in Example 3 using (S)-4-glycidyloxybenzo(b)furan-2-yl methyl ketone (0.52 g) obtained in Starting Material Synthesis Example 71 and 4-(naphthalen-2-yl)piperidine (0.47 g), (S)-4-(2-hydroxy-3-(4-naphthalen-2-yl)piperidino)propyloxy)benzo(b)furan-2-yl methyl ketone (0.87 g) was obtained as a brown oil. This was dissolved in ethyl acetate and maleic acid (0.22 g) was added. The precipitated crystals were recrystallized from a mixed solvent of isopropanol-ethyl acetate to give the title compound (0.76 g) as pale-yellow crystals, melting point 153-155° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].C(O)=[O:28]>>[CH2:22]([O:21][P:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:28])[NH:10][C:9]([NH2:11])=[N:8][C:7]1=2)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: O=CO
Reactant: CCOP(=O)(CCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Product: CCOP(=O)(CCCCOn1cnc2c(=O)[nH]c(N)nc21)OCC
Yield: 76 %

Procedure:
A solution of 6-chloro-9-[4-(diethoxyphosphoryl)butoxy]-2-formamidopurine (0.220 g, 0.54 mmol) in 80% formic acid (5 ml) was stirred at 80° C. for 5 hr. The solvent was evaporated under vacuum and the residue coevaporated with toluene (2×10 ml). The residue was chromatographed on silica gel (eluted with chloroform-ethanol 9:1) to give the title compound (0.148 g, 76%). 1H NMR: δH ((CD3)2SO) 1.22 (6H, t, J=7 Hz, (OCH2CH3)2), 1.64 (2H, m, CH2P), 1.79 (4H, m, CH2CH2), 3.9 (4H, m, (OCH2CH3)2), 4.26 (2H, t, NOCH2), 6.67 (2H, br.s, D2O exchangeable, NH2), 7.96 (1H, s, H-8), 10.75 (1H, br.s, D2O exchangeable, NH).
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@@H:9]2[CH:25]=[C:24]3[C@@:12]([CH3:35])([C@@H:13]4[C@@H:21]([CH2:22][CH2:23]3)[C@:20]3([OH:26])[C@@:16]([CH3:34])([C@@H:17]([C:27]5[CH:33]=[CH:32][C:30](=[O:31])[O:29][CH:28]=5)[CH2:18][CH2:19]3)[CH2:15][CH2:14]4)[CH2:11][CH2:10]2)[C@H](O)[C@H](O)[C@H]1O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:35][C@@:12]12[C@H:13]3[CH2:14][CH2:15][C@:16]4([CH3:34])[C@@H:17]([C:27]5[CH:33]=[CH:32][C:30](=[O:31])[O:29][CH:28]=5)[CH2:18][CH2:19][C@:20]4([OH:26])[C@@H:21]3[CH2:22][CH2:23][C:24]1=[CH:25][C@@H:9]([OH:8])[CH2:10][CH2:11]2
Reactant: C[C@@H]1O[C@@H](O[C@@H]2C=C3CC[C@@H]4[C@H](CC[C@]5(C)[C@@H](c6ccc(=O)oc6)CC[C@]45O)[C@@]3(C)CC2)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 87.5 %

Procedure:
Proscillaridin (3 g, 5.6 mmol) was dissolved in ethanol (57 ml) at 40° C. while stirring, to this solution was added 171 ml of sodium acetate buffer (pH=4, 0.02 M) at 40° C., followed by naringinase (1.03 g). The reaction was stirred for 24 hours, when ethanol was added (200 ml) and the solvent was removed in vacuo, an additional 100 ml ethanol was added and the solvent was removed in vacuo. Material was purified by flash chromatography (DCM to 9:1 DCM:MeOH) to give 9 as an off-white solid (1.9 g, 4.9 mmol, 90%). 1H-NMR (CDCl3, 300 MHz): 7.89 (dd, J=9.7, 2.6 Hz, 1H), 7.26 (dd, J=2.6, 0.9 Hz, 1H), 6.27 (dd, J=9.7, 0.9, 1H), 5.31 (s, 1H), 4.31 (m, 1H), 2.47 (dd, J=9.3, 6.2 Hz, 1H), 2.25-0.98 (m, 19H), 1.04 (s, 3H), 0.73 (s, 3H) 13C-NMR (CDCl3, 75 MHz): 163.28, 148.77, 147.59, 146.42, 123.90, 123.35, 115.22, 85.01, 67.65, 51.20, 50.38, 48.46, 42.65, 40.82, 37.58, 35.71, 32.65, 32.36, 29.17, 28.89, 28.76, 21.43, 19.10, 16.69.
Reaction SMILES: [CH:1](=[N:8][C:9]1C=CC=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NCCC[Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].[SiH4]>C1(C)C(C)=CC=CC=1>[C:2]1([CH:1]=[N:8][CH2:9][CH2:10][CH2:11][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: CO[Si](CCCN)(OC)OC
Agent: [SiH4]
Solvent: Cc1ccccc1C
Product: CO[Si](CCCN=Cc1ccccc1)(OC)OC
Temperature: 90 °C

Procedure:
25 grams (0.138 moles) of N-benzylidene aniline [cas no. 538-51-2, from TCI America] was combined with 24.7 grams (0.138 moles) of gamma-aminopropyltrimethoxysilane [cas no. 13822-56-5, Silquest A-1110 Silane from Crompton Corporation] and 100 grams of xylene. The resulting slurry was warmed to 90° C. for one hour before a vacuum of 20 mm Hg was applied. Distillation of the xylene and aniline resulted in 36 grams (98%) of N-benzylidene aminopropyltrimethoxysilane [cas no. 67674-55-9] by GC analysis.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])[CH3:3].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(N(CC)CC)C>C(O)C.ClCCl>[NH2:20][C:19]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:2][CH3:3])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCc1ccccc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccccc1-n1ncc(C#N)c1N
Temperature: 60 °C

Procedure:
A solution of 3.0 g (17.0 mmol) of 2-ethylphenylhydrazine hydrochloride and 2.12 g (17.0 mmol) of ethoxymethylenemalononitrile in 36 ml of ethanol is mixed with 7.1 ml (51.1 mmol) of triethylamine and heated at 60° C. until the reaction is complete according to a TLC check (about 30 min). For working up, the solvent is stripped off, and the residue is taken up in dichloromethane, washed with saturated sodium bicarbonate solution and dried over sodium sulphate. Concentration results in a crude product which is purified by column chromatography on silica gel (mobile phase dichloromethane with 0-10% methanol). 3.05 g (83.5% of theory) of the desired product are obtained.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[H][H].[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]>CN(C)C=O>[N+:1]([C:4]1[N:8]=[C:7]([C:20]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:13])[CH:21]=2)[NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: O=Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc([N+](=O)[O-])n[nH]2)cc1F
Temperature: 70 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
10 ml of a N,N-dimethylformamide solution of 3.4 g of 3-nitro-1,2,4-triazole was added dropwise to a suspension of 1.2 g (60%) of sodium hydride and 50 ml of N,N-dimethylformamide under cooling with ice. After generation of hydrogen stopped, 4.3 g of 2,4-difluorobenzaldehyde was added, followed by stirring at 70° C. for 3 hours. The mixture was concentrated under reduced pressure, 200 ml of water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with diisopropyl ether to obtain 1.6 g of 4-(3-nitro-1,2,4-triazolyl)-2-fluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH:13]=O)[C:4](=[O:15])[CH:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([Cl:1])=[CH:3][C:4]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(Cl)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To 20 mL of a chloroform solution containing 179 mg of (4-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 286 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 47 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 269 mg of sodium triacetoxyborohydride was added and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=50:1], to give 177 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([S:14][C:15](=S)[NH:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CC[CH2:21][CH2:20]1>>[CH2:7]([S:14][C:15]1[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:20]([CH3:21])[NH:17][N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCl
Reactant: C1CCOC1
Reactant: NNC(=S)SCc1ccccc1
Product: COC(=O)c1c(SCc2ccccc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At room temperature, 47 g of methyl 2-chloroacetate is added to a solution of 55 g of dithiocarbazic acid-S-benzyl ester in 250 ml of tetrahydrofuran. After stirring for 16 hours at room temperature, the precipitated solids mixture is filtered and washed with diethyl ether, and the residue is stirred into 200 ml of 12% strength ammonia solution. The product has the sulfur removed from it by extraction with methylene chloride. After drying over sodium sulfate, the methylene chloride is distilled off and the solid which remains is recrystallized from ethyl acetate. Melting point: 109°-110° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[CH:8][C:9]=2[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:4]=[N:3]1.[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:16])=[CH:8][C:9]=2[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:4]([C:19]2[CH:20]=[CH:21][C:22]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:23][C:18]=2[CH3:17])=[N:3]1
Reactant: CCN(CC)c1cc(C)nc2cnn(C)c12
Reactant: Cc1cc(-n2cccn2)ccc1B(O)O
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: CCN(CC)c1cc(C)nc2c(-c3ccc(-n4cccn4)cc3C)nn(C)c12
Temperature: 100 °C
Reaction time: 16 h
Yield: 7.2 %

Procedure:
A mixture of compound 13a (40 mg, 0.13 mmol), compound 2c (41 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol), aqueous sodium carbonate (0.3 mL of a 2 M solution, 0.6 mmol), toluene (2 mL), and ethanol (2 mL) was heated at 100° C. with stirring for 16 hr in a sealed vial. The mixture was cooled, filtered, and purified by preparative HPLC to afford [1,5-dimethyl-3-(2-methyl-4-pyrazol-1-yl-phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-diethyl-amine (compound 13-1, 3.5 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[N:3]=1.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1>>[ClH:1].[ClH:1].[NH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:3]=2)[CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCC(C)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(Cl)nc21
Product: CCC(C)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(NC3CCC(N)CC3)nc21
Product: Cl
Yield: 99.5 %

Procedure:
The operation is carried out as in Stage 2 of Example 44 starting from 201 mg of the product obtained in Stage 1 above and 595 mg of trans-1,4-diaminocyclohexane. In this way 139 mg of expected product is obtained in the form of crystals.
Reaction SMILES: O[C:2]1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]2)[O:4][CH2:3]1.S(Cl)(Cl)=O.O.Cl>N1C=CC=CC=1>[C:19]1([C:18]#[C:17][C:2]2[CH2:3][O:4][C:5]3([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]3)[CH:6]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)(C#Cc1ccccc1)CO2
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)N1CCC2(C=C(C#Cc3ccccc3)CO2)CC1
Reaction time: 2 h
Yield: 20.5 %

Procedure:
To a solution of Compound 26a (93 mg, 0.282 mmol) stirred in pyridine (4 mL) at 0° C. was added thionyl chloride (0.103 mL, 1.141 mmol) and the reaction mixture was stirred at 0° C. to r.t. for 2 h. Afterwards, it was poured into water, acidified with 1M HCl and extracted with chloroform. The organic layers were combined, washed with brine, dried over sodium sulphate and evaporated to dryness to afford a crude, which was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 92:8 to 75:25) to give 18 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:28])[C:26]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]3[CH:23]=2)=[CH:10][CH:9]=1)=[O:6].Cl.[CH3:30][NH:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:30][N:31]([CH3:32])[C:26]1[C:25]([F:28])=[CH:24][C:4]([C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]4[CH:23]=3)=[CH:12][CH:13]=2)=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(F)c(F)c4)cc3)cn2c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(N(C)C)c(F)c4)cc3)cn2c1
Temperature: 120 °C
Yield: 79.5 %

Procedure:
A stirred mixture of 3,4,5-trifluoro-N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]benzamide (0.10 g, 0.26 mmol), dimethylamine hydrochloride (0.087 g, 1.07 mmol) and potassium carbonate (0.147 g, 1.07 mmol) in dry DMSO (3 ml) was heated at 120° C. for 22.5 h. After cooling to room temperature, the reaction mixture was added to water (100 ml) and the precipitate was collected by vacuum filtration, and washed with water (40 ml). The solid was dried in an oven at 95° C., and then purified by flash chromatography (25:1 DCM/MeOH) to give the title compound (0.084 g, 80%) as a colourless solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 60 °C
Yield: 19.5 %

Procedure:
The intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.38 mmol) from Example 21B was treated with thiomorpholine-1,1-dioxide (154 mg, 1.14 mmol), tetrabutylammonium iodide (140 mg, 0.38 mmol) and N,N′-diisopropylethylamine (135 μL, 0.76 mmol) in N,N′-dimethylformamide (2 mL). The mixture was heated to 60° C. for 56 h and cooled to room temperature. Water was added and the solid filtered off and dried. The crude solid was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) and the obtained solid triturated with water and drops of methanol, then filtered off and dried under high vacuum to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea (46.40 mg, 20%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (bs, 1H), 9.04 (bs, 1H), 8.56 (s, 1H), 7.57 (d, 2H), 7.40-7.37 (m, 2H), 7.25 (d, 1H), 6.97 (d, 1H), 6.47 (s, 1H), 4.25-4.21 (m, 2H), 4.00 (s, 3H), 3.34 (bs, 4H), 2.93 (bs, 4H), 2.68-2.64 (m, 2H), 1.99-1.96 (m, 2H), 1.18 (s, 9H); LC-MS (ESI) m/z 625 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([C:15]2[CH:33]=[C:32](B(O)O)[C:18]3[O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:22][C:21]=4[C:17]=3[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:3]=[C:4]([C:25]2[C:20]3[O:19][C:18]4[CH:32]=[CH:33][C:15]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:16][C:17]=4[C:21]=3[CH:22]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cc(-c2ccccc2)cc2c1oc1ccc(-c3ccccc3)cc12
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
Product: Brc1cccc(-c2cc(-c3ccccc3)cc3c2oc2ccc(-c4ccccc4)cc23)c1
Temperature: 110 °C
Yield: 42.1 %

Procedure:
In a 100 mL three-neck flask were put 1.7 g (6.0 mmol) of 3-bromoiodobenzene and 2.2 g (6.0 mmol) of 2,8-diphenyldibenzofuran-4-boronic acid. The air in the flask was replaced with nitrogen. To this mixture were added 30 mL of toluene and 6.0 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 0.35 g (0.30 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was refluxed at 110° C. for 4 hours. After reaction, the aqueous layer was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give an oily substance, and the oily substance was dissolved in about 10 mL of toluene. This solution was suction-filtered through Celite (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The resulting filtrate was concentrated to give an oily substance, and hexane was added to the oily substance. The mixture was irradiated with ultrasonic waves, whereby a solid was precipitated. This solid was collected by suction filtration to give 1.2 g of a white powder in 44% yield, which was the substance to be produced.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:2].[ClH:17]>O1CCOCC1>[Cl-:17].[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:2]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Solvent: C1COCCO1
Product: N#CC=C1CC[NH2+]CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(cyanomethylidene)piperidine-1-carboxylate (20 g, 90 mmol) was dissolved in 4M HCl in dioxane and allowed to stir at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3](C)=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[NH3:15].[CH3:16]O>>[NH2:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)[C:16]#[N:15]
Reactant: N
Reactant: Cc1c(Br)cc(C(F)(F)F)cc1C#N
Reactant: CO
Product: N#Cc1cc(CN)cc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
3-Bromomethyl-5-trifluoromethyl-benzonitrile (which is prepared in Reference Example 12) (15.9 g) is dissolved in 7M-ammonia/methanol (550 ml), and the mixture is stirred at 50-60° C. for 30 minutes. The reaction solution is concentrated under reduced pressure. To the resulting residue are added a saturated aqueous sodium bicarbonate solution and chloroform, and the mixture is separated, and the organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1 chloroform:methanol: ammonium hydroxide solution=19:1:0.1) to give 3-aminomethyl-5-trifluoromethyl-benzonitrile (10.4 g). MS (m/z): 201 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C1(P(=[CH:34][C:35](OCC)=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C.C(O)C>C([O-])(=O)C=C>[NH:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:34][C:35]1=[O:36]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C=CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Synthesis of intermediates containing A2-77 (V═O) is shown in Scheme 54. Utilizing the procedure published by Doherty et. al (see WO 03/0999284), Wittig homologation of commercially available 2,4-dinitrobenzaldehyde (251) with ethyl (triphenylphosphoranylidene)-acetate results in propenoate 252. Catalytic hydrogenation in the presence of glacial acetic acid and ethanol results in the target 1H-quinolin-2-one 253 which, utilizing the same oxidation/reduction sequence as shown in Scheme 53 results in hydrazine 254 (R15, V═O) and iodide (255). At the conclusion of the synthesis that utilizes 254 or 255, reduction of the amide with LAH under standard conditions provides an optional synthesis of intermediates containing A2-77 (V═H2).