Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.Cl>C(O)C>[O:10]=[C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]12
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Product: O=C(O)c1ccc2nc3ccccc3c(=O)n2c1
Yield: 44.5 %

Procedure:
A reaction mixture containing 4.35g (31.8 mmol) of anthranilic acid, 5.00g (31.8 mmol) of 6-chloronicotinic acid, 3ml of conc. HCl and 80ml of ethanol was heated at reflux for 21 hours. The mixture was cooled and filtered to give 3.40g (38.9%) of the expected product, mp. 323° -325° dec. The analytical sample was obtained by recrystallization from methanol-ether, mp. 323° -325° dec.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[CH:40]12[N:46]([C:47](=O)[CH2:48]Br)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2>>[CH:40]12[N:46]([CH2:47][CH2:48][O:10][C:8]3[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]4[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=4[C@@H:14]4[CH2:23][CH2:22][C:21]5[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=5[CH2:15]4)=[CH:35][CH:34]=3)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CBr)N1C2CCC1CC2
Product: COc1cc(NCCCc2ccc(OCCN3C4CCC3CC4)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 99.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.3 mg) was obtained.
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[N:10][CH:9]1[C:16]#[N:17])(OC(C)(C)C)=O.O1CCOCC1.[ClH:24]>O1CCOCC1>[ClH:24].[NH2:15][CH2:14][C:12]1[CH:13]=[N:8][C:9]([C:16]#[N:17])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1C=C(CN)C=NC1C#N
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ncc(CN)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 Eq. of N-Boc-5-aminomethyl-2-cyanopyrimidine was introduced into dioxane at RT and, after addition of dioxane/HCl (5M), stirred at RT for 3 h. After conversion of the precursor was complete (TLC check: mobile phase A), the reaction mixture was concentrated and poured into ether. The precipitated solid was filtered off with suction, again dissolved in MeOH and poured into ether. The product was filtered off with suction and dried under high vacuum to afford 89% of the theoretical yield of 5-aminomethyl-2-cyanopyrimidine hydrochloride. FAB-MS (M+)=134
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]=[CH:33][N:34]=[C:35]([O:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:36]=2[N:37]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:28]2[CH:29]=[CH:30][C:31]3[N:32]=[CH:33][N:34]=[C:35]([O:38][CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[C:36]=3[N:37]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(OC4CCOCC4)c3n2)cnc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene sulfonamide (0.114 g, 0.290 mmol) (Intermediate 5), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.070 g, 0.263 mmol), 1 N aq. sodium bicarbonate (0.527 ml, 0.527 mmol) and PdCl2(dppf)-CH2Cl2Adduct (22.0 mg, 2.60 μmol) in dioxane (1.5 ml) was subjected to microwave irradiation for 1 hour at 110° C. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.030 g, 23%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.75-1.98 (2H, m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H, m), 5.58-5.72 (1H, m), 7.50-7.70 (3H, m), 7.85 (1H, d, J=7.6 Hz), 8.45 (1H, d, J=8.4 Hz), 8.58-8.72 (2H, m), 8.87 (1H, s), 9.04 (1H, br s), 10.55 (1H, s). m/z=498.09 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21](Cl)[C:20](Cl)=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.N1C(NC(C2C(=O)N3C(SC4C=C(F)C(F)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(F)C=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(Cl)C=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(F)C([C:118]([F:121])([F:120])[F:119])=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(Cl)C(F)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(F)C(Cl)=CC=43)=NC=2)=O)=NN=N1>>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[CH:21][C:20]([C:118]([F:121])([F:120])[F:119])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1
Reactant: O=C(Nc1nnn[nH]1)c1cnc2sc3cc(Cl)c(Cl)cc3n2c1=O
Reactant: O=C(Nc1nnn[nH]1)c1cnc2sc3cc(F)c(C(F)(F)F)cc3n2c1=O
Agent: O=C(Nc1nnn[nH]1)c1cnc2sc3cc(Cl)c(F)cc3n2c1=O
Agent: O=C(Nc1nnn[nH]1)c1cnc2sc3cc(Cl)ccc3n2c1=O
Agent: O=C(Nc1nnn[nH]1)c1cnc2sc3cc(F)c(Cl)cc3n2c1=O
Product: O=C(Nc1nnn[nH]1)c1cnc2sc3ccc(C(F)(F)F)cc3n2c1=O

Procedure:
N-(5-tetrazolyl)-7,8-dichloro-4-oxo-4H-pyrimido[2,1-b]-benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7,8-difluoro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-8-fluoro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-8-chloro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-trifluoromethyl-8-fluoro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-fluoro-8-chloro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; and N-(5-tetrazolyl)-7-chloro-8-fluoro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:22](=[O:23])[C:21]([C:24]([NH2:26])=[O:25])=[C:20]([OH:27])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:16]([C:17]2=[O:18])=[C:15]([OH:29])[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:3]>CC([O-])=O.CC([O-])=O.[Pd+2].CO>[CH3:1][N:2]([C@@H:4]1[C:22](=[O:23])[C:21]([C:24]([NH2:26])=[O:25])=[C:20]([OH:27])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:16]([C:17]2=[O:18])=[C:15]([OH:29])[C:14]2[C:9](=[C:10]([C:4]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:5]=3)[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:3]
Reactant: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(-c5ccccc5)c4C[C@H]3C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
7-iodosancycline, 150 mg (0.28 mM), Pd(OAc)2 and 10 mL of MeOH are added to a flask with a stir bar and the system degassed 3× using argon. Na2CO3 (87 mg, 0.8 mM) dissolved in water and argon degassed is added via syringe is added along with phenylboronic acid (68 mg, 0.55 mM) in MeOH that was also degassed. The reaction was followed by HPLC for 2 hours and cooled to room temperature. The solution was filtered, and dried to produce a crude mixture. The solid was dissolved in dimethylformamide and injected onto a preparative HPLC system using C18 reverse-phase silica. The fraction at 36-38 minutes was isolated, and the solvent removed in vacuo to yield the product plus salts. The salts were removed by extraction into 50:25:25 water, butanol, ethyl acetate and dried in vacuo. This solid was dissolved in MeOH and the HCl salt made by bubbling in HCl gas. The solvent was removed to produce the product in 42% yield as a yellow solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[CH2:12][O:11]C(C)(C)[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]>CO>[C:1]([O:6][CH2:7][CH:8]([OH:9])[CH2:12][OH:11])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC1COC(C)(C)O1
Solvent: CO
Product: CCCC(=O)OCC(O)CO
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 22 (50.6 g, 250 mmol), and Dowex 50W X8-100 H+ resin (76.5 g) in MeOH (500 ml), was heated at 50° C. for 2 hours, cooled to room temperature, filtered, and the resin washed with MeOH (1×200 ml). The methanol fractions were combined and concentrated in vacuo. The crude product was passed through a plug of silica gel using ethyl acetate:hexanes (1:1) as the eluent. Fractions containing the product were combined and concentrated in vacuo to afford 23 (32.8 g, 200 mmol, 81%) as an oil. The material was used in the next step without any further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:26])[O:17][CH2:18][C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>Br.CC(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:26])[O:17][CH2:18][C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C1OCC(c2ccncc2)=C1c1ccc(O)cc1
Yield: 138.2 %

Procedure:
A mixture of 3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (1.0 g, 0.002 mol) in 33% HBr/AcOH (50 mL) was refluxed for 3 h. The reaction mixture was quenched with a saturated NaHCO3 solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-(4-hydroxyphenyl)-4-(pyridin-4-yl)furan-2(5H)-one (0.7 g, 95%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:3][CH2:6][CH:7]([CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: CC(CO)CCCCOc1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(CCl)CCCCOc1ccccc1

Procedure:
A solution of 60 g of thionyl chloride in 50 ml of CHCl3 was added dropwise to 100 g of 1-Hydroxy-2-methyl-6-phenoxyhexane in 200 ml of CHCl3 and 0.5 ml of DMF. The solution was refluxed until the development of the gas was finished and then poured onto ice. The aqueous phase was extracted twice with CHCl3 and the combined organic phases were washed with water and finally with a saturated NaHCO3 -solution, dried with MgSO4, evaporated and the residue was distilled off. Boiling point0.5 : 117° - 120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1.[ClH:34].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:34].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:22]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CN(C)c1ccc(CNc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(Br)cc1)CCC2

Procedure:
7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.47 g) and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]-amine (0.70 g) as starting materials were reacted and treated in the same manner as in Example 12. The obtained solid was dissolved in ethyl acetate (4 mL). Thereto was added 4 mol/L-HCl/ethyl acetate (0.35 mL), and the precipitated solid was collected by filtration to give N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.65 g). melting point: 104-113° C.
Reaction SMILES: Cl.[Br:2][C:3]1[C:8]2[N:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]([C@@H:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]>O1CCOCC1.CO>[Br:2][C:3]1[C:8]2[N:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:10]([C@@H:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
4N HCl in dioxane (0.5 mL) was added to a solution of [(S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (128 mg, 0.24 mmol) in MeOH (3 mL) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo and the resulting residue purified by HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90% 0.1% HCO2H in acetonitrile/water) to afford 178 (88 mg, 81%). LCMS (Method K): RT 3.82 min [M+H]+ 451.9/453.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.19-7.86 (3H, m), 7.70 (1H, dd, J=8.75, 4.59 Hz), 7.64-7.33 (5H, m), 7.26 (1H, t, J=9.22 Hz), 5.22 (1H, s), 1.56 (3H, d, J=6.87 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11]C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Br)c(O)c1
Temperature: 50 °C
Yield: 78.1 %

Procedure:
To a 500 mL round bottom flask charged with 2-bromo-5-nitroanisole (11.0 g, 47 mmol) was added 100 mL of anhydrous DCM. Aluminum chloride (25 g, 150 mmol) was then added to the reaction mixture. The resulting suspension was heated overnight under nitrogen at 50° C. The reaction was allowed to cool to rt, poured over ice, and acidified to pH 4 with the addition of aqueous 10% HCl. The resulting mixture was filtered through a bed of Celite and the filtrate was transferred to a separatory funnel. The aqueous phase was extracted with methylene chloride (˜2×200 mL). The combined organic phase was dried over Na2SO4 and conc in vacuo giving the crude title compound which was purified by silica gel chromatography (330 g) using EtOAc/hexanes (1:1) as eluent to afford the title compound (8.0 g, 78%) m/z: 217.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[C:14]([C:19]([O:21]C)=[O:20])=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[OH-].[Li+].Cl.[OH-].[Na+]>C(OCC)C.C1COCC1.CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:14]([C:19]([OH:21])=[O:20])=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1nccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1nccnc1Oc1ccc(Nc2ccccn2)cc1

Procedure:
To a 250 mL round-bottomed flask containing methyl 3-(4-(pyridin-2-ylamino)phenoxy)pyrazine-2-carboxylate (7.44 g, 23.1 mmol) was added the mixed solvent of THF/MeOH/water. The tan solution was stirred at room temperature with addition of lithium hydroxide (1.66 g, 69.2 mmol). A white precipitate quickly formed. The suspension was acidified to pH 3 with 1 N HCl:diethyl ether, basified to pH 9 with 10 N NaOH, and reneutralized to pH 7 with concentrated HCl. The precipitate was collected by filtration and identified as the product. MS (ESI, pos. ion) m/z: 309.0 (M+1). IC50 (uM) 18.835.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][NH:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH:23]3[CH:21]([CH:22]3[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])[CH2:20]2)=[N:17][CH:18]=1)=[O:12].Cl.Cl[CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.C(Cl)Cl>CCCCCCC.CN(C=O)C>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][NH:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:20][CH:21]3[CH:23]([CH:22]3[N:25]([S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:27])=[O:28])[CH2:41][CH2:42][N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH2:24]2)=[N:17][CH:18]=1)=[O:12]
Reactant: O=C(NOC1CCCCO1)c1cnc(N2CC3C(C2)C3NS(=O)(=O)c2ccc3ccccc3c2)nc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2)S(=O)(=O)c2ccc3ccccc3c2)nc1
Reaction time: 0.08 h
Yield: 19.8 %

Procedure:
NaH (0.223 g, 5.5 mmol) was washed with heptane (10 ml), then suspended in DMF (5 ml). N-(Tetrahydro-2H-pyran-2-yloxy) 2-{6-[(naphthalene-2-sulfonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide (0.991 g, 1.95 mmol) was added, and the mixture stirred for 5 min. To NaH (0.172 g, 4.3 mmol) in DMF was added 1-(2-chloroethyl)-pyrrolidine hydrochloride (0.724 g, 4.2 mmol). The reaction was swirled gently for 2 min, and then added to the solution of N-(tetrahydro-2H-pyran-2-yloxy) 2-{6-[(naphthalene-2-sulfonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide. The mixture was stirred at r.t. for 5 days, then poured into DCM (150 ml) and quenched with 2.4M ammonium chloride solution (50 ml). The organic layer was separated, and the aqueous was further extracted with DCM (150 ml). The combined organic extracts were dried, concentrated in vacuo to give the title compound (0.234 g, 19%). This was carried forward without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH:4]([CH2:8]O)[C:5]([OH:7])=[O:6]>P(=O)(O)(O)O>[CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[CH2:8])[C:5]([OH:7])=[O:6]
Reactant: CC(C)CC(CO)C(=O)O
Agent: O=P(O)(O)O
Product: C=C(CC(C)C)C(=O)O
Temperature: 270 °C

Procedure:
4-Methyl-2-(hydroxymethyl)pentanoic acid (8.7 g) is heated with 10 drops of 85% phosphoric acid in a Wood's metal bath at 220° C. for 20 minutes. A distillation head is attached and the pressure is slowly decreased to 60 mm while the temperature is increased to 270° C. Product starts to distill and the pressure is further decreased to 10 mm. The vapor temperature varies between 180° and 190° C. The yield of the title compound as distillate is 7.0 g.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][N:5]=1>C(OCC)(=O)C.C(O)C>[NH2:1][CH:2]([CH3:13])[CH2:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(N)Cc1ncccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(N)Cc1ncccc1N
Yield: 100.1 %

Procedure:
2-aminopropyl-3-nitropyridine (171) (6.3 g, 35 mmol) is dissolved in 100 mL 1/1 ethyl acetate/ethanol in a Parr shaker bottle. Nitrogen is bubbled through the solution for 2 minutes followed by the addition of 10% Pd/C (500 mg). The suspension is hydrogenated on a Parr apparatus under 40 psi of H2 until hydrogen uptake ceased. The suspension is filtered through Celite and the solvent evaporated in vacuo to afford 5.3 g of the 2-aminopropyl-3-aminopyridine (182). 1-propyl-2-chloromethyl-7-azabenzsmidazole
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+]>CO.[Zn]>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)c1cccc(N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To the solution of 213A: (1 g, 4.64 mmol) in MeOH (23.19 ml) was added ammonium chloride (2.481 g, 4.64 mmol) and zinc dust (1.516 g, 23.19 mmol). The reaction was stirred at rt for 2 h, then warmed to 60° C. for 1 h. The reaction was filtered through a pad of Celite, rinsing with MeOH. The filtrate was concentrated. The residue was partitioned between EtOAc and water and the layers were separated. The organic layer washed with sat. NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography afforded 213B (0.85 g, 99% yield) as a yellow oil. MS (ESI) m/z: 186.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][C:8]2=[O:14])=[CH:3][CH:2]=1>CC(O)=O.O=[Pt]=O>[CH3:13][N:10]1[CH2:11][CH2:12][N:7]([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)[C:8](=[O:14])[CH2:9]1
Reactant: CN1CCN(c2ccncc2)C(=O)C1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CN1CCN(C2CCNCC2)C(=O)C1
Reaction time: 72 h

Procedure:
A mixture of 1-(pyridin-4-yl)-4-methyl-2-piperazinone (12 mg, 0.063 mmol) and PtO2 (49 mg) in HOAc (6.0 mL) was hydrogenated on a Parr shaker under 40 psi for 3 days. The mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was dissolved in 1N HCl (5.0 mL). The solution was then concentrated in vacuo to give the titled compound as hydrochloride salt (12 mg). MS 198.5 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:38]=[C:26]1[CH2:27][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[NH:21]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: Cc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)cc1

Procedure:
Prepared from (3-amino-4′-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G16) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a white solid (76 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].CC1CC=CCC=1>C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCC1OCCO1)Cc1ccccc1
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCNCCC1OCCO1
Yield: 90.4 %

Procedure:
To a stirred solution of N-(2-(1,3-dioxolan-2-yl)ethyl)-N-benzyl-2-((tert-butyldimethylsilyl)oxy)ethanamine (3.87 g, 10.6 mmol) in ethanol (100 mL) was added 10% palladium on carbon (1.93 g) and 1-methyl-1,4-cyclohexadiene (5.93 mL, 53.0 mmol). The suspension was heated at reflux for 30 minutes and allowed to cool. The suspension was filtered through celite and the filter cake washed with further ethanol. The solvent was evaporated at reduced pressure to afford the title compound (2.64 g, 91%).