Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:19]1[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][NH:24][CH2:25]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.CC(C)([O-])C.[Na+]>>[CH2:12]([N:19]1[C@@H:26]2[C@@H:21]([CH2:22][CH2:23][N:24]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:25]2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccnc1
Reactant: c1ccc(CN2C[C@@H]3CCNC[C@@H]32)cc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: c1ccc(CN2C[C@@H]3CCN(c4cccnc4)C[C@@H]32)cc1
Yield: 57 %

Procedure:
The product from Example 33E and 3-bromopyridine were processed according to the procedure of Example 1E, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used. The residue was purified by chromatography (SiO2, hexanes: ethyl acetate, 20:80, Rf. 0.2) to provide the title compound (0.16 g, 57% yield). 1H NMR (CD3OD, 300 MHz) δ2.04 (m, 2H), 2.56 (m, 1H), 3.00 (m, 2H), 3.22 (m, 2H), 3.55 (m, 1H), 3.60 (d, J=12.5 Hz, 1H), 3.70 (d, J=12.5 Hz, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 7.04 (ddd, J=8.8, 3.0, 1.3 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 7.24 (m, 5H), 7.80 (dd, J=4.7, 1.3 Hz, 1H), 7.84 (d, J=3.0 Hz, 1H); MS (DCI/NH3) m/z 280 (M+H)+.
Reaction SMILES: [Na].[S:2]([C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([OH:5])(=[O:4])=[O:3].[Na].[Cl-].[Ca+2:22].[Cl-]>O>[Ca:22].[S:2]([C:6]1[CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[C:8]([CH:7]=1)[C:16]([O:18][CH3:19])=[O:17])([OH:5])(=[O:4])=[O:3]
Reactant: [Ca+2]
Agent: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)O)c1
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: [Ca]
Temperature: 30 °C

Procedure:
296 Grams of dimethyl 5-sulfoisophthalate sodium salt were placed together with 2000 g of ion exchanged water in a reactor equipped with a stirrer. The contents in the reactor were heated with stirring to 80° C. so that the sodium salt was dissolved in water. A solution of calcium chloride dissolved in an amount of 55.5 g into 900 g of ion exchanged water was then gradually added dropwise to the thus obtained solution. The resulting mixture was cooled to 30° C. and filtered to separate white precipitates. The precipitates were dispersed in 3000 g of ion exchanged water. The dispersion was heated to 80° C., maintained at that temperature for 1 hour, cooled to 30° C. and then filtered. The precipitates were washed with water. Such a procedure including dispersion, heating, filtration and washing steps was repeated once more. The thus obtained precipitates were dried at 120° C. for 5 hours to obtain 156 g of dimethyl 5-sulfoisophthalate calcium salt (Compound of the above formula (2)) as a white powder. The atomic absorption analysis revealed that the 5-sulfoisophthalic acid calcium salt powder contained 6.8% by weight of calcium.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@H:35]([CH2:38][CH3:39])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]([CH2:36][OH:37])[CH2:38][CH3:39])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC[C@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (R)-2-bromo-N-(1-hydroxybutan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C20H21FN4O3S, 416.13; m/z found, 417.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.32 (m, 2H), 8.16-8.12 (m, 1H), 7.96 (m, 1H), 7.68-7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.40-7.30 (m, 3H), 3.43-3.35 (m, 1H), 3.33 (d, J=5.9, 1H), 3.12-3.05 (m, 1H), 1.60-1.48 (m, 1H), 1.42-1.28 (m, 1H), 0.79 (t, J=7.4, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)=[O:8].C[Li].[CH2:16](O)C.[Cl-].[Na+]>C(OCC)C>[O:11]1[CH:12]=[CH:13][C:9]([C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])([OH:8])[CH3:16])=[CH:10]1
Reactant: Cc1ncoc1C(=O)c1ccoc1
Reactant: CCO
Agent: [Cl-]
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ncoc1C(C)(O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-Furyl 4-methyl-5-oxazolyl ketone (1 g) in dry diethylether (15 ml) at -70° C. under a nitrogen atmosphere was treated dropwise with methyllithium (1.5M solution in diethylether, 4.1 ml). After 45 minutes the reaction mixture was allowed to warm to room temperature and ethanol (2 ml) was added. The mixture was poured into saturated aqueous sodium chloride and extracted with dichloromethane. Chromatography and crystallisation then gave 1-(3-furyl)-1-(4-methyl-5-oxazolyl)ethanol identical to the material obtained in (a) above.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:14](=O)[CH2:15]Br)([CH3:10])([CH3:9])[CH3:8].N.O>C(O)C>[C:22]([C:19]1[CH:18]=[C:13]([C:14]2[N:1]=[C:2]3[N:6]([CH:15]=2)[CH:5]=[CH:4][S:3]3)[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:20]=1[OH:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: Nc1nccs1
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2cn3ccsc3n2)cc(C(C)(C)C)c1O
Yield: 38.3 %

Procedure:
In 20 ml of ethanol were dissolved 1.2 g of 2-aminothiazole and 3.9 g of 3,5-di-tert-butyl-4-hydroxyphenacyl bromide, and the solution was refluxed for 2 hours. The reaction mixture was neutralized by the addition of aqueous ammonia and added 30 ml of water. The crystals thus precipitated were recovered by filtration and recrystallized from ethanol to provide 1.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazo[2,1-b]thiazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl>CN(C)C=O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: ClCc1ccccn1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.8 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). 2-Picolyl chloride hydrochloride (4.44 g, 27.1 mmol) was added to this suspension, and stirred for 14 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (2.98 g, 57%).
Reaction SMILES: [Li].[N+:2]([CH:5]([CH3:7])[CH3:6])([O-:4])=[O:3].[CH3:8][C:9]1[CH:10]=[C:11]([C:15](=[O:22])[C:16]([N+]([O-])=O)([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1>CN(C)P(N(C)C)(N(C)C)=O>[N+:2]([C:5]([CH3:7])([CH3:6])[C:16]([CH3:17])([CH3:18])[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=1)=[O:22])([O-:4])=[O:3]
Reactant: Cc1cccc(C(=O)C(C)(C)[N+](=O)[O-])c1
Reactant: CC(C)[N+](=O)[O-]
Agent: [Li]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cccc(C(=O)C(C)(C)C(C)(C)[N+](=O)[O-])c1
Reaction time: 18 h
Yield: 48 %

Procedure:
The lithium salt of 2-nitropropane (0.52 mol.) was dissolved in 700 ml. of hexamethylphosphoramide and, while under nitrogen, 62.1 g. (0.3 mol.) of 3'-methyl-α-nitroisobutyrophenone was added. The reaction mixture was stirred 18 hours under fluorescent lighting. The mixture was then diluted with 1400 ml. of water and the aqueous mixture was extracted three times with 800 ml. portions of ether. The combined ether extracts were washed three times with water, dried over magnesium sulfate and the ether removed. The residue was crystallized from hexane to give a 48 percent yield of 3-nitro-2,2,3,3'-tetramethylbutyrophenone: m.p. 50°-51° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:30]2[S:34][N:33]=[C:32]([CH3:35])[N:31]=2)=[C:26]([CH:29]=1)[CH:27]=O.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[C:30]1[S:34][N:33]=[C:32]([CH3:35])[N:31]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc(-c2nc(C)ns2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nc(C)ns2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 19.7 %

Procedure:
A solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (110 mg, 0.43 mmol) and 5-methoxy-2-(3-methyl-1,2,4-thiadiazol-5-yl)-benzaldehyde (100 mg, 0.43 mmol) in acetic acid (5 mL) is warmed to 50° C. for 12 hours then at 80° C. for 60 hours. The reaction mixture is cooled to room temperature and poured into water and NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (40 mg, 20%). LCMS (ESMS): m/z 472.20 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](/[CH:26]=[CH:25]/[C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(/C=C/c2cc([N+](=O)[O-])cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-nitroquinazolin-4-ol (50 mg) in N,N-dimethylformamide (2 mL) was added 4-vinylbenzoic acid (35 mg), followed by palladium acetate (2.6 mg), tri-o-tolylphosphine (7.1 mg) and N,N-diisopropylethylamine (0.24 mL). The reaction mixture was heated at 120° C. for 24 h, then was cooled to room temperature and concentrated in vacuo. The residue was triturated with 50% (v/v) methanol/dichloromethane (2 mL). The resulting solid was isolated by filtration, washed sequentially with diethyl ether and water, then was dried in vacuo to give the title compound (36 mg). 1H NMR (300 MHz, DMSO-d6/CF3CO2H) δ8.75 (d, J=2.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.43 (d, J=4.5 Hz, 1H), 7.99-7.88 (m, 3H), 7.74 (d, J=8.4 Hz, 1H), 7.67-7.51 (m, 2H), 7.38 (dd, J=8.7, 2.6 Hz, 1H). HPLC Method B 8.26 min. MS (APCI−) m/z 496, 498.
Reaction SMILES: Br[C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.C([Li])CCC.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH4+].[Cl-]>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-4-chloropyrrolo[2,3-d]pyrimidine (Example 35) (232 mg; 1 mmol) in anhydrous THF (5 mL) was cooled to -78° C. under argon and a solution of n-butyl lithium (1.3 mL of 2.31M) was added at such a rate that the temperature of the reaction mixture remained below -72° C. After stirring the reaction mixture at -78° C. for 45 minutes, a solution of ethyl chloroformate (0.15 mL) in THF (2 ml) was added slowly, maintaining the reaction temperature below -72° C. The reaction mixture was stirred at -78° C. for 2 hours then allowed to warn to room temperature. A saturated solution of NH4Cl (20 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried and evaporated to a white solid, yield 210 mg (92%): m.p. 140°-141° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[CH2:21](S(O)(=O)=O)C.CCCCCC>C(OCC)(OCC)OCC>[Cl:20][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[N:1]=[CH:21][N:8]2[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(CNc2ncnc(Cl)c2N)cc1OC
Reactant: CCS(=O)(=O)O
Solvent: CCOC(OCC)OCC
Solvent: CCCCCC
Product: COc1ccc(Cn2cnc3c(Cl)ncnc32)cc1OC

Procedure:
To a suspension of 15.6 g (52.8 mmols) of 5-amino-4-chloro-6-(3,4-dimethoxybenzylamino)pyrimidine in 100 ml of triethyl orthoformate was added 149 mg (1.36 mmols) of ethanesulfonic acid and the resulting mixture was heated at 80° for 15 min. Upon cooling and addition of hexane to the reaction mixture, a yellow precipitate formed which was collected by filtration; yield, 15.4 g (95.6%) mp 159°-163°. Recrystallization from EtOH--H2O gave the analytical sample; yield 13.2 g (82.2%) mp 160°-164°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[C:18]([C:17]([NH2:16])=[O:24])=[N:20][CH:19]=[CH:15][CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ncccc1-c1c[nH]nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 4-(3-[4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0° C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl-2-pyridinecarboxamide as a white solid (67% yield), mp: 230-231° C. Anal. Calc'd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.O.[NH2:29][NH2:30]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:29][N:30]=[C:19]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=C(Cc1cccnc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CCO
Product: O=c1c2c(Cc3cccnc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 76 %

Procedure:
The procedure of Example 1 was repeated using a suspension of 4-hydroxy-3-[1-oxo-2-(pyridin-3-yl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (16 mg, 0.045 mmol, prepared in Synthetic Example 3) in ethanol (5 ml), and hydrazine monohydrate (80%, 10 μl, 0.25 mmol, 5.5 eq.) to obtain 5-phenyl-3-(pyridin-3-yl)methyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (yield: 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[N:18]([O:19][CH3:20])[CH3:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.00 g, 13.93 mmol), N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.94 g, 15.32 mmol) and 1-hydroxybenzotriazole (2.07 g, 15.32 mmol) were placed in a 100 mL round bottomed flask and dissolved in DMF (30 mL). Diisopropylethylamine (6.1 mL, 34.82 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 2.60 g (72% yield) of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:29]([O:36][C:37]([NH:39][CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:2][O:3][CH:4]=[C:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[CH2:41][CH2:42]1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Tetrahydrofuran (280 ml) was added to (methoxymethyl)triphenylphosphonium chloride (27.8 g, 81.1 mmol) and a solution (50.0 ml, 80.0 mmol) of 1.6M n-butyllithium in n-hexane was dropwise added at -40° C. over 30 minutes, which was followed by stirring for one hour. Then, a solution of 4-(benzyloxycarbonylamino)cyclohexanone (20.0 g, 81.0 mmol) dissolved in tetrahydrofuran (200 ml) was dropwise added over 30 minutes. The mixture was warmed to room temperature and stirred for 3.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the extract and the organic layer were combined. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give 7.02 g of 4-(benzyloxycarbonylamino)cyclohexylidenemethyl methyl ether as a colorless solid (32%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:6]=1)[C:2]#[CH:3].[N:27]([CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[N+:28]=[N-:29].C1CCN2C(=NCCC2)CC1>CO.[Cu]I>[N:32]1([CH2:31][CH2:30][N:27]2[CH:3]=[C:2]([CH2:1][NH:4][C:5]3[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[CH:6]=3)[N:29]=[N:28]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: [N-]=[N+]=NCCN1CCCCC1
Reactant: C#CCNc1cc(Nc2ccc(C3CCOCC3)cc2)ncc1C(N)=O
Agent: [Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC(=O)c1cnc(Nc2ccc(C3CCOCC3)cc2)cc1NCc1cn(CCN2CCCCC2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 4-(prop-2-ynylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide (Example 184) (20 mg, 0.057 mmol) was dissolved in 6 mL MeOH. To it were added 1-(2-azidoethyl)piperidine (18 mg, 0.11 mmol), DBU (26 μL, 0.17 mmol) and finally powder CuI (13 mg, 0.068 mmol). The mixture was stirred at RT for 5 h, filtered and subjected to reverse phase prep HPLC to isolate the title compound. MS found for C27H36N8O2 as (M+H)+ 505.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.14 (1H, s), 8.12 (1H, s), 7.39 (2H, dt, J=8.4; 2.0 Hz), 7.24 (2H, dt, J=8.4; 2.0 Hz), 6.20 (1H, s), 4.60 (2H, s), 4.05 (2H, m), 3.73 (2H, m), 3.59 (4H, m), 3.04 (2H, m), 2.87 (1H, m), 1.95 (2H, m), 1.86-1.75 (8H, m) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3CO2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[C:30]([N:33]1C2C(=CC=C(N)C=2C(OC)=O)[C@H]2CCO[C@H]2[CH2:34]1)(=[O:32])[CH3:31].BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[C:30]([N:33]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])(=[O:10])=[O:11])[C:22]=2[C:23]([O:25][CH3:26])=[O:24])[C@H:17]2[CH2:29][CH2:28][O:27][C@H:18]2[CH2:34]1)(=[O:32])[CH3:31]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Reactant: COC(=O)c1c(N)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from methyl cis-(3aRS,9bRS)-5-acetyl-7-amino-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 29) and 2-bromo-4-fluorobenzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].Cl>C(N(CC)CC)C.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>[CH3:25][Si:26]([C:29]#[C:30][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1)([CH3:28])[CH3:27]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(C(=O)c1ccc(Oc2ccc(Br)cc2)cc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Oc2ccc(C(=O)C(=O)c3ccccc3)cc2)cc1
Yield: 100.4 %

Procedure:
4-(4-Bromophenoxy)benzil (3.81 g, 0.01 mole), trimethylsilylacetylene (1.96 g, 0.02 mole), and dichlorobis(triphenylphosphine)palladium (0.30 g) in triethylamine (20 ml) were placed under a nitrogen atmosphere in a sealed flask and heated at 66°-68° C. for four hours. The cooled brown reaction mixture was poured into cold dilute hydrochloric acid to yield a brown oil which was extracted with methylene chloride. The methylene chloride solution was washed with dilute aqueous hydrochloric acid and water, dried over magnesium sulfate, and concentrated on a rotary evaporator to yield a brown gum (4.0 g). The gum was extracted with boiling cyclohexane (100 ml) (small amount remained insoluble) and the solution treated with charcoal, filtered, and concentrated to yield 4-[(4-[trimethylsilyl)ethynyl]phenoxy]benzil as an orange gum (3.4 g, 85% yield). MS, no M+, major fragment m/e 293 [+CO--C6H4 --O--C6H4 --C≡C--Si(CH3)3 ].