Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:14][CH3:15])[NH:5][C:6](=O)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)([Cl:18])=O>C(OC(=O)C)C>[Cl:18][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl

Procedure:
A solution of ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (60 g, 0.26 mole) and phosphorous oxychloride (POCl3, 320 mL) was heated under reflux for 4 to 5 h (monitor reaction by TLC using 30% ethylacetate and hexanes). After completion of reaction, phosphorous oxychloride was removed on a rotary evaporator. The residue was poured on to ice water and extracted with ethylacetate several times. The combined organic layers were evaporated, on a rotary evaporator, to give crude ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g). This compound was used without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]([CH3:9])=[CH:7][N:6]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[N:5]=1.[H-].[Na+].[CH3:18]I>C1COCC1>[CH3:18][O:1][CH2:2][CH2:3][C:4]1[C:8]([CH3:9])=[CH:7][N:6]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:11])=[O:12])[N:5]=1
Reactant: Cc1cn(S(=O)(=O)N(C)C)nc1CCO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1nn(S(=O)(=O)N(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2-hydroxyethyl)-N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.2, 636 mg, 2.73 mmol) in THF (10 mL). Sodium hydride (131 mg, 60% in mineral oil, 3.27 mmol) was added at 0° C. and stirred for 30 min at 0° C. This was followed by the addition of CH3I (204 μL, 3.28 mmol). The reaction mixture was stirred for 3 h at room temperature. The reaction was quenched with 10 mL of NH4Cl (sat.) and the aqueous phase was extracted with 3×50 mL of EtOAc. The combined organic phases were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography with hexanes/EtOAc (15:1-8:1) as the eluent to give 452 mg (67%) of the title compound as a yellow oil.
Reaction SMILES: Cl.Cl.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([C@@:24]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[CH3:25])=[CH:23][C:16]=3[N:15]=2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].C(N(CC)CC)C.[CH3:47][C:48]1[CH:65]=[CH:64][C:51]([C:52](OC2C=CC([N+]([O-])=O)=CC=2)=[O:53])=[CH:50][CH:49]=1>C(Cl)Cl>[CH3:47][C:48]1[CH:65]=[CH:64][C:51]([C:52]([NH:5][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][C:22]([C@@:24]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:26]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:27])[CH3:25])=[CH:23][C:16]=4[N:15]=3)=[CH:8][CH:7]=2)=[NH:4])=[O:53])=[CH:50][CH:49]=1
Reactant: Cc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccc(C)cc3)cc1)n2C
Temperature: 50 °C

Procedure:
A suspension of 0.7 g (1.2 mmol) of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride in 25 ml of methylene chloride is combined with 4.0 ml (28 mmol) of triethylamine and 0.8 g (3.0 mmol) of 4-nitrophenyl 4-methyl-benzoate and heated to 50° C. for 3.5 hours, whereupon a clear solution is formed. After cooling, it is washed with sodium bicarbonate solution, saline solution and water, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on silica gel, eluting with ethyl acetate/ethanol (50:1 and 9:1). The uniform fractions are combined, concentrated by evaporation, triturated with ether, suction filtered and dried.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11]>O>[CH2:1]([C:15]1[CH:16]=[CH:17][C:10]([OH:11])=[CH:12][C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCCCCO
Solvent: O
Product: CCCCCCCCc1ccc(O)cc1O

Procedure:
4-n-octyl resorcinol is prepared by heating 1-octanol with resorcinol in the presence of 20 wt % alumina. The 1-octanol is added at such a rate that the temperature is maintained at 275° C, with continuous removal of the water formed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>>[NH2:17][C:12]1[C:11]2=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:7]=[CH:6][CH:5]=3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: CN(C)C(=O)Nc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 9 %

Procedure:
Using a procedure similar to that of Example 5 with 7-(3-amino-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and dimethylcarbamyl chloride as starting materials, 26 mg (9%) of the desired product was Isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.0 (s, 6 H); ES-MS m/z 503.26 [M+H]+, HPLC RT (min) 2.66.
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH:8]1[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1>CCCCCC.C1COCC1>[Li:5][C:8]1([Si:7]([CH3:19])([CH3:20])[CH3:6])[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cnc2c(c1)CCCC2[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21

Procedure:
A mixture of a 1.55 molar solution of butyl lithium in hexane (6.45 ml, 1O mM) and THF (10 ml) maintained below 10° was treated with a solution of 5,6,7,8-tetrahydro-8-trimethylsilyl-3-methylquinoline (2.2 g, 10 mM) in THF (1O ml) to obtain 5,6,7,8-tetrahydro- -8-lithio-8-trimethylsilyl-3-methylquinoline. After 0.5 hour a 22% solution of t-butyldimethylsilyl isothiocyanate in benzene (6.9 g, 1O mM) was added dropwise. After 0.5 hour the reaction mixture was quenched with 2N hydrochloric acid (25 ml) and after 1 hour the aqueous layer was separated, basified (to pH9) and extracted with dichloromethane (2×50 ml). The organic extracts were dried and evaporated to give the title thioamide (2.1 g, c 100%). Recrystallisation from benzene gave analytically pure material (1.9 g, 88%) m.p. 153°, identical to authentic material (Found: C63.7; H,6.9; N,13.4% C11H14N2S requires: C64.0; H,6.8; N,13.6%).
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][N:9]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:8]=12.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[C:12]1([C:11]2[C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=3[N:9]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[N:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1nccc2c(-c3ccccc3)nn(-c3ccsc3)c12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]ccc2c(-c3ccccc3)nn(-c3ccsc3)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 7-methoxy-3-phenyl-1-(3-thienyl)-1H-pyrazolo[3,4-c]pyridine (28.5 mg) in acetonitrile (10 mL) were added sodium iodide (27.8 mg) and chloro(trimethyl)silane (81 mg), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give the title compound (24.5 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1.CS(O)(=O)=O.[C:25](=O)(O)[O-:26].[Na+]>CO>[CH3:1][O:2][CH:3]([O:26][CH3:25])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:10]=1
Reactant: O=C([O-])O
Reactant: CCCCCCCCOc1ccc(C=COC)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCOc1ccc(CC(OC)OC)cc1

Procedure:
A solution of 1-(2-methoxyethenyl)-4-(octyloxy)benzene (3.67 g) and methanesulfonic acid (0.5 ml) in methanol (30 ml) is refluxed for 30 min, cooled, and neutralized with 1.0N aqueous sodium bicarbonate (10 ml). The mixture is evaporated in vacuo, and the residue dissolved in ether, dried with sodium sulfate, filtered, and evaporated to leave 1-(2,2-dimethoxyethyl)-4-(octyloxy)benzene as a colorless oil. This acetal may be used directly in step C below (as in example 2). Alternatively, the acetal is dissolved in a 1:1 mixture of THF and 3N hydrochloric acid, refluxed for one hour, and cooled. The mixture is extracted with dichloromethane, and without drying the dichloromethane extracts are concentrated to provide crude 4-(octyloxy)phenylacetaldehyde as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([N+:18]([O-])=O)[CH:5]=1)[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[NH2:18][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OCC)c(OCC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCC)c(OCC)cc1N
Yield: 99.9 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of ethyl 4,5-diethoxy-2-nitrobenzoate (7.17 g, 25.3 mmol) and Pd/C (10%, 0.7 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford ethyl 2-amino-4,5-diethoxybenzoate as a solid (6.401 g, 99%)1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 6.14 (s, 1H), 5.60 (br, 2H), 4.30 (q, 2H), 4.05 (m, 4H), 1.44 (t, 3H), 1.38 (m, 6H); LC-MS (ESI) m/z 254 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1([CH3:24])[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17](=O)[CH2:16]1>C1COCC1>[CH3:14][C:15]1([CH3:24])[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17](=[CH:5][C:3]#[N:4])[CH2:16]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=CC#N)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
60% NaH dispersion in mineral oil (0.96 g, 24 mmol) was added to a solution of diethyl cyanomethylphosphonate (4.25 g, 24 mmol) in THF (30 ml) while cooling with ice water. The mixture was stirred for 30 min and a solution of 3,3,5,5-tetramethylcyclohexanone (3.08 g, 20 mmol) in THF (10 ml) was added dropwise. Cooling bath was removed and the mixture was stirred at room temperature for 72 h. It was poured into ice water (100 ml) and extracted with diethyl ether (350 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 20 (2.38 g, 71%) as a colorless oil. 1H-NMR (CDCl3, TMS):0.97 and 1.01 (total 12H, both s, 3′,5′-CH3); 1.36 (2H, s, 4′-CH2); 2.01 (2H, s, 2′-CH2); 2.26 (2H, s, 6′-CH2) and 5.14 ppm (1H, s, ═CH).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(c1ccc(O)cc1)C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1

Procedure:
In analogy to the procedure of Example III, the title compound is prepared from 21.5 g (0.113 mol) of the compound from Example VII, 25 g (0.116 mol) of 2-chloromethylquinoline hydrochloride and 35.15 g (0.254 mol) of potassium carbonate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9](=[O:28])[N:10]([C:21]2[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1)[NH2:34].C(O)(C)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[N:10]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)=[C:31]([O:30][CH3:29])[CH:32]=2)[N:22]=1)[C:9](=[O:28])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(N(C(=O)OCc2cccnc2)c2ccnc(Cl)n2)c(OC)c1
Reactant: COc1cc(N)ccc1N1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(N(C(=O)OCc2cccnc2)c2ccnc(Nc3ccc(N4CCN(C)CC4)c(OC)c3)n2)c(OC)c1
Temperature: 60 °C

Procedure:
A resealable tube was charged with (2-chloro-pyrimidin-4-yl)-(2,4-dimethoxy-phenyl)carbamic acid pyridin-3-ylmethyl ester (0.100 g, 0.249 mol), 3-(methyloxy)-4-(4-methyl-1-piperazinyl)aniline (0.100 g, 0.45 mmol), and isopropanol (2 mL). Trifluoroacetic acid (0.074 g, 0.050 mL, 0.65 mmol) was added. The tube was sealed and the mixture was heated at 60° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated to afford a pale purple oil. The resulting solution was diluted with ethyl acetate and the mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-100% dichloromethane-(90:10:1, dichloromethane/methanol/ammonium hydroxide)) to afford 3-pyridinylmethyl 2,4-bis(methyloxy)-phenyl(2-((3-(methyloxy)-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-pyrimidinyl)-carbamate as an off-white solid. MS (MH+) 586; Calculated 585.66 for C31H35N7O5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[I-].[Na+]>C1COCC1>[N:24]1([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:23])=[CH:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cn2ccnc2)cc1
Yield: 27.4 %

Procedure:
4-((1H-Imidazol-1-yl)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), imidazole (0.062 g; 0.907 mmol) and sodium iodide (0.152 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 20 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.021 g (41%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu]I>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:22]=2)=[CH:13][CH:12]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(=O)n(-c3ccccn3)n2)cc1
Yield: 3.6 %

Procedure:
In a 50 mL round bottom flask, 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one (250 mg, 0.71 mmol), 2-bromopyridine (105 μL, 1.07 mmol), copper(I)iodide (13.6 mg, 0.07 mmol), and potassium carbonate (296 mg, 2.14 mmol) in dimethylformamide (10 mL) was heated to reflux 14 h. The reaction was cooled and water (20 mL) was added. The sticky solids were filtered off and then partitioned between methylene chloride and water, separated, and dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 10 mg (2.4%) oil. MS m/z 391 (M+H).
Reaction SMILES: C(OC(C1C=CC([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[C:13]2[C:19]#[N:20])=CC=1)=O)C.[BH4-].[Na+]>ClCCCl>[OH:18][CH2:17][C:15]1[CH:14]=[C:13]([C:19]#[N:20])[NH:12][CH:16]=1
Reactant: CCOC(=O)c1ccc(-n2cc(C=O)cc2C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: N#Cc1cc(CO)c[nH]1
Reaction time: 1 h
Yield: 142.8 %

Procedure:
To a solution of 1-(4-ethoxycarbonylphenyl)-4-formylpyrrole-2-carbonitrile (2.0 g) in 1,2-dichloroethane (10 ml) was added sodium borohydride (296 mg) in one portion under nitrogen at ambient temperature. The mixture was stirred for one hour at the same temperature and then quenched with aqueous saturated ammonium chloride solution at 5° C. The organic layer was washed with water and brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted by a mixture of ethyl acetate and n-hexane (2:1) to give 4-ethoxycarbonylphenyl)-4-hydroxymethylpyrrole-2-carbonitrile (1.3 g) as a white solid.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:32]([NH:34][C@H:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[CH2:36][OH:37])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.[ClH:46]>[Pd].CO>[ClH:46].[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([NH:16][C@H:15]([C:32]([NH:34][C@H:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:36][OH:37])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc([C@H](CO)NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc([C@H](CO)NC(=O)[C@H](CCCN)NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1(e) above from (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(S)-N-[2-hydroxy-1 -(4-methoxyphenyl)-ethyl]ornithine amide (2.85 g; from step (c) above), 10% Pd/C (1.40 g), MeOH (200 mL) and concentrated HCl (2 mL) under hydrogen for 6 hours to give the crude product as a solid (2.6 g). Pure sub-title compound was obtained by crystallization from MeOH:diethyl ether to give a white solid (1.58 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]2[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]2[CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccn2cc(C(C)(C)C)nc12
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cn2cccc(CO)c2n1

Procedure:
From 2g (yield: 52%) as an oil; IR (CCl4) 2962, 1498 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (s, 9H), 4.72 (s, 2H), 5.01 (s, 1H), 6.39 (t, 1H, J=7 Hz), 6.73 (d, 1H, J=7 Hz), 7.03 (s, 1H), 7.67 (d, 1H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 30.1, 32.2, 62.4, 106.8, 111.6, 124.4, 129.1, 143.9, 156.4; MS m/z 204 (M+, 53), 203 (100), 175 (24), 171 (55).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14]3([CH2:18][S:17][C:16]([N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:15]3)[C:10]3([CH2:13][O:12][CH2:11]3)[C:9]([CH3:35])([CH3:34])[O:8][C:5]2=[CH:6][CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].C.[ClH:52]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=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>[ClH:52].[CH3:34][C:9]1([CH3:35])[C:10]2([CH2:11][O:12][CH2:13]2)[C:14]2([CH2:18][S:17][C:16]([NH2:19])=[N:15]2)[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)[CH:3]=2)[O:8]1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CS1)c1cc(Br)ccc1OC(C)(C)C21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(-c3cncnc3)cc2C2(CSC(N)=N2)C12COC2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
A mixture of di-tert-butyl (6′-bromo-2′,2′-dimethyldispiro[oxetane-3,3′-chromene-4′,4″-[1,3]thiazol]-2″-yl)imidodicarbonate (268 mg, 0.471 mmol), pyrimidin-5-ylboronic acid (175 mg, 1.41 mmol), bis(triphenylphosphine)palladium(II) dichloride (33.0 mg, 0.047 mmol) and Na2CO3 (150 mg, 1.41 mmol) in dioxane-water (4:1, 5.4 mL) was stirred for 1.5 hours at 100° C. Tetrakis(triphenylphosphine)palladium(0) (272 mg, 0.235 mmol) was added to the mixture and the mixture was stirred for 1.5 hours at 100° C. To the mixture was added charcoal and the mixture was stirred for 30 minutes at 50° C. The mixture was filtered through celite pad (eluted with EtOAc) and the filtrate was washed with water and brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated at reduced pressure. To the residue were added toluene (2.7 mL) and silica gel (neutral; 804 mg), and the mixture was stirred for 1 hour at 110° C. After concentration of the reaction mixture at reduced pressure, the residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%), then re-purified with column chromatography on amino silica gel (Hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%). The purified product was dissolved in dioxane (5.0 mL) and HCl (4 M in dioxane, 0.049 mL, 0.198 mmol) was added. The mixture was stirred for 2 hours at ambient temperature. After concentration at reduced pressure, the residue was triturated with IPE, collected by filtration and washed with IPE. The solid was dried under reduced pressure at 30° C. to afford 2′,2′-dimethyl-6′-(pyrimidin-5-yl)dispiro[oxetane-3,3′-chromene-4′,4″-[1,3]thiazol]-2″-amine hydrochloride (62.6 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]#[N:25])=[CH:14][CH:13]=2)(C)(C)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[NH2:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]#[N:25])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C#N)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2cccs2)c2cc(C#N)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Tert-butyl[6-cyano-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.17 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate diisopropyl ether to give 3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarbonitrile hydrochloride (0.14 g, 93.3%) as crystals.