Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[F:28][CH:29]([F:33])[C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:27][C:30](=[O:31])[CH:29]([F:33])[F:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(NC(=O)C(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
A mixture of crude 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg), difluoroacetic acid (0.0186 mL, 0.296 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75.5 mg, 0.394 mmol), 1-hydroxybenzotriazole (53.2 mg, 0.394 mmol) and triethylamine (0.0824 mL, 0.591 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 3 h, and diluted with ethyl acetate. The resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture and NH silica gel eluting with a 30% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (42.4 mg, 0.0812 mmol).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:34][N:33]([CH3:35])[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:2]([CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH3:1])=[CH:28][CH:29]=1
Reactant: CNCCN1c2ccccc2COc2ccccc21
Reactant: CN(C)c1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCc1ccc(N(C)C)cc1)CCN1c2ccccc2COc2ccccc21
Temperature: 90 °C

Procedure:
5,11-Dihydro-5-[2-(N-methylamino)ethyl]dibenzo[b,e][1,4]oxazepine (254 mg, 1.00 mmol), 4-dimethylaminophenethyl mesylate (365 mg, 1.50 mmol), sodium carbonate (160 mg, 1.50 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (20 ml), and they were heated under reflux at 90° C. for 7 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (100:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-[N-(4-dimethylaminophenethyl)-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (184 mg, 46%).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[S:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:14][CH:13]=1)=[O:21]
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Yield: 96 %

Procedure:
Methyl 2-({2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethyl}thio)benzoate (4.630 g, 11.502 mmol) was take up in DCM (50 ml) and treated with trifluoroacetic acid (44.40 g, 389.405 mmol) at r.t for 4 h. The mixture was evaporated and azeotroped with toluene. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 3.825 g of [4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl)phenoxy]-acetic acid (yield for two steps 63.9% overall).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:12]([N+:23]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[Ni]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:12]([NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1Nc1ccccc1F
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-(benzyloxy)-N-(2-fluorophenyl)-3-nitropyridin-2-amine (2.00 g, 5.89 mmol) in dioxane (100 mL) was added Raney nickel (346 mg, 5.89 mmol). The mixture was stirred under hydrogen at room temperature for 12 h, filtered through Celite® and concentrated to give 6-(benzyloxy)-N2-(2-fluorophenyl)pyridin-2,3-diamine as an oil. The residual oil was dissolved in DCM (50 mL) and CDI (629 mg, 3.88 mmol) was added. After stirring at room temperature for 12 h the mixture was concentrated and purified by column chromatography to give the title compound (643 mg). LCMS m/z=336.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>C(#N)C>[C:19]([S:21][C@@H:11]1[CH2:12][CH2:13][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:10]1)(=[O:22])[CH3:20]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)O[C@H]1CCN(c2nc(C(N)=O)cs2)C1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@@H]1CCN(c2nc(C(N)=O)cs2)C1
Yield: 89.8 %

Procedure:
To a solution of (3S)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (1.15 g) (obtained as described in Reference Example 20(8)) in acetonitrile (35 ml) was added potassium thioacetate (1.35 g, 11.8 mmol) at room temperature, and the mixture was heated under reflux for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→2% methanol in ethyl acetate as the eluant to afford (3R)-3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (962 mg, yield 90%) as a pale brown solid.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]3[CH2:25][CH2:24][O:23][C:22]3=[O:26])[C:6]2=[N:5][C:4]=1[CH3:27])=[O:2].[BH4-].[Na+].O>C(O)C>[OH:2][CH2:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]3[CH2:25][CH2:24][O:23][C:22]3=[O:26])[C:6]2=[N:5][C:4]=1[CH3:27]
Reactant: Cc1cccc(N2CCOC2=O)c1COc1cccn2c(C=O)c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(N2CCOC2=O)c1COc1cccn2c(CO)c(C)nc12
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A solution of 3-[2-(3-formyl-2-methylimidazo[1,2-a]pyridin-8-yloxymethyl)-3-methylphenyl]oxazolidin-2-one (1.39 g, 3.8 mmol) and sodium borohydride (0.19 g, 4.75 mmol) in anhydrous ethanol (125 ml) is stirred at RT for 1.5 h. Water (100 ml) is then added, the ethanol is distilled off on a rotary evaporator and the aqueous residue is stirred at 4° C. for 30 min. The precipitate is filtered off, washed with cold water and dried in vacuo. The title compound (1.28 g, 91%) is obtained as a beige solid. M.p. 190-193° C.
Reaction SMILES: [S:1]1C2C=CC(C(C3C4C(=C(CSC)C=CC=4)NC=3)CCC#N)=CC=2[CH:3]=[CH:2]1.F[C:28]1[C:36]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])=[C:35]2[C:31]([C:32]([CH:42]([C:47]3[CH:52]=[CH:51][C:50](C(F)(F)F)=[CH:49][CH:48]=3)[CH2:43][CH2:44][C:45]#[N:46])=[CH:33][NH:34]2)=[CH:30][CH:29]=1>>[S:1]1[C:50]2[CH:51]=[CH:52][C:47]([CH:42]([C:32]3[C:31]4[C:35](=[C:36]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:28]=[CH:29][CH:30]=4)[NH:34][CH:33]=3)[CH2:43][CH2:44][C:45]#[N:46])=[CH:48][C:49]=2[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12
Product: CS(=O)(=O)Cc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12

Procedure:
The title compound was prepared starting from 284 mg (0.75 mmol) of the compound from Example 52 in analogy to the synthesis of the compound from Example 72. 409 mg (54% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[Li+].[BH4-].C1COCC1>C1COCC1.CO.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:8][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32]([NH:33][CH3:34])=[O:35])=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:11]=1[Cl:12]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
A solution of 54.3 g (84.0 mmol) of crude methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate in 351 mL of anhydrous THF and 39 mL of anhydrous MeOH was cooled in an ice water/brine bath to −5° C. (internal temperature). To the stirred solution was added 125 mL (251 mmol) of 2M LiBH4/THF via addition funnel at a rate so as to maintain the temperature below 5° C. The addition required 35 minutes. The brine bath was then replaced by an ice water bath and stirring of the solution continued. After another 1.5 hours LCMS indicated complete reaction. The solution was quenched by addition of 200 mL of saturated aqueous sodium bicarbonate followed by 400 mL of water and 600 mL of EtOAc. The mixture was stirred vigorously for 30 minutes and then transferred to a separatory funnel. After the phases separated, solid remained in the aqueous phase so an additional 200 mL of water was added and the mixture shaken, and the phases again separated. The aqueous solution was extracted with EtOAc (2×200 mL). The combined EtOAc solutions were washed with 5% aqueous NaCl (1×), saturated brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure to afford 54.5 g of 6-(N-(4-bromo-3-chloro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide as an orange-brown foam. The crude material was carried forward to the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.54 (m, 1H) 8.12 (s, 1H) 7.98 (dd, J=8.93, 5.41 Hz, 2H) 7.59 (d, J=2.73 Hz, 1H) 7.54 (d, J=2.63 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.22 (s, 1H) 5.64 (t, J=5.56 Hz, 1H) 4.48 (d, J=5.56 Hz, 2H) 3.45 (s, 3H) 2.84 (d, J=4.59 Hz, 3H) 2.06-2.17 (m, 1H) 0.75-1.06 (m, 3H) 0.47 (br. s., 1H). LCMS (ESI): 623 (M+H+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([C:11]1[N:12](S(C)(=O)=O)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]#[N:21])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)([OH:10])[CH3:9])(C)(C)C.[OH-].[Na+].Cl>CO.O>[OH:10][C:8]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]#[N:21])=[C:15]([C:22]([F:25])([F:23])[F:24])[CH:14]=2)([CH3:9])[CH2:7][OH:6]
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1cc2cc(C#N)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)(CO)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-1-methyl-ethyl]-1-methanesulfonyl-6-trifluoromethyl-1H-indole-5-carbonitrile (9.22 g, 0.01935 mole) in methanol (150 mL), a solution of NaOH (4.64 g 0.1161 mole) in water (25 mL) was added. The resulting mixture was heated in an oil-bath at 50° C. for 4 hr and tthen stirred at room temperature overnight. To the reaction mixture was then added 1 N HCl until the pH was 3. The aqueous mixture was extracted with EtOAc, the organic layer was washed with water, brine, then dried over MgSO4. The solvent was stripped off, the residue was triturated with DCM, and the resulting solid collected by filtration to yield the title compound as a light grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[CH:4][C:3]=1[OH:9]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 2,5-dichlorophenol (10 g, 61.3 mmol) in CCl4 (400 mL) at 0° C. was dropwise added 4.7 mL (73.6 mmol) of 70% HNO3 in 30 mL of CCl4 during 30 min. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The yellow precipitate was collected by filtration and dried to give the desired product (8.4 g) at 62% yield. MS (DCI/NH3) m/z 224.91 (M+NH4)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 7.17 (s, 1 H) 8.25 (s, 1 H) 12.12 (s, 1 H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:10]=1[O:11][C:12]1[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[C:15]2[N:20]=[C:19]([C:21]3[CH:35]=[C:34]([CH3:36])[C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([CH3:37])[CH:22]=3)[O:18][C:16]=2[N:17]=1>ClCCl>[F:8][C:9]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:10]=1[O:11][C:12]1[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:37])[C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:34]([CH3:36])[CH:35]=3)[O:18][C:16]=2[N:17]=1
Reactant: CCCc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
55 μl of trifluoroacetic acid were added to a solution of 39 mg of tert-butyl {-4-[5-(2,5-difluorophenoxy)-7-propyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate in 0.4 ml of dichloromethane, and the mixture was stirred at room temperature for 16 h. The reaction was then concentrated under reduced pressure, and the residue was triturated with diisopropyl ether, filtered off with suction and dried. This gave 21 mg (60%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:14]1[NH:13][C:2]1[C:3]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1nn(C)c2c(Cl)ncnc12
Reactant: NC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)c2c(NC3Cc4ccccc4C3)ncnc12
Yield: 62 %

Procedure:
7-chloro-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidine (28 mg, 0.15 mmol) (see J. Med. Chem.,31, 454 (1988)), 2-aminoindan (66 mg, 0.50 mmol), and triethylamine (30 μl, 0.2 μmol) in dry methylene chloride (1 ml) were heated to reflux for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:4) to obtain the title compound (26 mg, 0.093 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6](=[CH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)CC(=Cc1cccc2ccccc12)C(=O)O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(Cc1cccc2ccccc12)C(=O)O
Yield: 98.9 %

Procedure:
To a solution of 251 mg of the propionic acid compound in 10 ml of methyl alcohol was added 30 mg of a 10% palladium charcoal, and the mixture was hydrogenated under a hydrogen atmosphere at room temperature. After filtration of the catalyst, the reaction mixture was concentrated under reduced pressure to obtain 250 mg of 3-methoxycarbonyl-2-(1-naphthylmethyl)propionic acid as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([I:34])=[CH:4][N:3]=1.[OH-].[NH4+:36]>O1CCOCC1>[NH2:36][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13](=[O:27])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH3:10])[C:5]([I:34])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: C[C@H](Nc1nc(Cl)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (64) (964 mg, 1.65 mmol) in anhydrous 1,4-dioxane (5 mL) in a sealed tube, ammonium hydroxide (6 mL) was added and the resulting mixture was stirred at 110° C. for 16 h. An additional amount of ammonium hydroxide (3 mL) was added to the reaction mixture and stirring was continued for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-8% MeOH-DCM) to afford the product, (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (65) (532 mg, 57% yield) as a light tan solid. ESI-MS m/z: 564.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][NH:5][C@@H:4]([C:7]([NH:9][C:10]2([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:8])[CH2:3]1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:1][C:2]1([CH3:23])[CH2:6][N:5]([CH2:30][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)[C@@H:4]([C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])[CH2:3]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D151) (100 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(4,4-dimethylpyrrolidine-2-carboxamido)cyclopropyl)benzoate (D108) (70 mg) and 4-(trifluoromethyl)-benzylbromide (0.041 ml). (Cs2CO3: 1.5 eq; reaction time: 20 hrs, RT)
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:37])C=CC=CC=1.[CH3:39][N:40](C)C=O.O1CCCC1>O>[CH2:30]([O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:40][CH3:39])=[O:7])=[C:11]([Cl:37])[CH:12]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[C:27]#[N:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Reaction time: 0.17 h

Procedure:
[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro phenyl]carbamic acid phenyl ester (1.17 g) was added to dimethylformamide (6 ml), and then amethylamine-containing 2N tetrahydrofuran solution (0.4 ml) was added and the mixture was stirred for 10 minutes. Water (15 ml) was added, and the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (968 mg)
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].[F:27][C:28]([F:45])([F:44])[C:29]1[CH:30]=[CH:31][C:32]([O:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[N:33][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN1CCCC1=O>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:40][C:39]4[CH:38]=[CH:37][C:36]([O:35][C:32]5[CH:31]=[CH:30][C:29]([C:28]([F:45])([F:27])[F:44])=[CH:34][N:33]=5)=[CH:43][CH:42]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCN(Cc4ccc(Oc5ccc(C(F)(F)F)cn5)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
(R)-2-Nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.50 g), 4-(5-trifluoromethylpyridin-2-yloxy)benzaldehyde (0.41 g), N-methylpyrrolidone (10 ml), and sodium triacetoxyborohydride (0.44 g) were mixed and stirred at room temperature for 16 hours. The reaction mixture was added to a 1 N sodium hydroxide aqueous solution. The precipitated crystal was collected by filtration. The crude crystal was purified by silica gel column chromatography (methylene chloride:ethyl acetate=8:2→methylene chloride:ethyl acetate=2:8) and recrystallized from acetone-ether to afford the title compound as a pale yellow powder (0.55 g).