Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]([O:24][CH2:25]C)=[O:23].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][C:15]5[C:20]([CH:21]=4)=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:10]=3)[N:5]=[CH:4][C:3]=2[C:22]([O:24][CH3:25])=[O:23])[CH2:33][CH2:32]1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of ethyl 4-chloro-6-quinolin-3-yl-1,5-naphthyridine-3-carboxylate (compound 41) (6.0 g, 17 mmol), 4-amino-1-N-Cbz-piperidine (compound 45) (4.1 g, 17 mmol), and potassium carbonate (4.6 g, 33 mmol) in N,N-dimethylacetamide (100 mL) was heated to 90° C. After 2 hours, the reaction was cooled to room temperature and filtered. The filtrate was concentrated and the residue was triturated with methanol to afford methyl 4-({1-[(benzyloxy)carbonyl]piperidin-4-yl}amino)-6-quinolin-3-yl-1,5-naphthyridine-3-carboxylate (compound 46) as a cream solid (8.2 g, 90%).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[N:3]=[C:2]([C:21]3[CH:20]=[N:19][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:23][CH:22]=3)[C:7]([OH:8])=[CH:6][CH:5]=2)=[CH:10][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Oc1ccc(-c2ccc(Cl)cc2)nc1-c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Yield: 59.6 %

Procedure:
A mixture of 2-bromo-6-(4-chlorophenyl)pyridin-3-ol (0.319 g, 1.12 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (277.8 mg, 1.46 mmol) and potassium carbonate (386.7 mg, 2.798 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (64.7 mg, 0.056 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 15 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow solid. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 50% ethyl acetate in hexanes to give 6-(4-chlorophenyl)-6′-(trifluoromethyl)-[2,3′-bipyridin]-3-ol (0.234 g, 60% yield) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:21])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23].O.O.O.[S:29]1[CH2:33][CH2:32][CH2:31][CH:30]1O.[OH-].[Na+:36]>O.C(O)C>[Na+:36].[S:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[NH:21][CH:13]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:11]([NH:10][CH:7]1[C:8](=[O:9])[N:4]2[CH:5]1[S:6][C:2]([CH3:25])([CH3:1])[CH:3]2[C:22]([O-:24])=[O:23])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Reactant: OC1CCCS1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)SC2C(NC(=O)C(NC3CCCS3)c3ccc(O)cc3)C(=O)N2C1C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a stirred suspension of 6.7 g (0.016 mol) of amoxicillin trihydrate in 125 ml of distilled water was added in one portion 16 ml of 1 N aqueous sodium hydroxide solution. The amoxillin quickly dissolved and after two minutes 4.99 g (0.048 mol) of tetrahydrothiophene-2-ol dissolved in 10 ml of absolute ethanol was added. After stirring for two minutes at 25° C. the solution was quickly frozen and lyophilized for 19 hr to give 8.36 g of {2S-[2α, 5α, 6β(S*)]}-6-{[tetrahydro-2-thienylamino-(4-hydroxyphenyl)acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt as a slightly yellow pungent smelling powder.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:4]([C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:3]
Reactant: C[Si](C)(C)C#CC1(O)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1-(2-trimethylsilyl-l-ethynyl)cyclohexanol (1.79 g, 9.13 mmol) in tetrahydrofuran (11 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Reactant: C1COCCN1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCOCC2)c1
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 29, morpholine was reacted with N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)-benzamide to give the title compound in 64% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.44 (m, 4H), 2.94 (s, 6H), 3.15 (m, 1H), 3.55 (t, 4H), 3.96 (m, 2H), 4.06 (m, 1H), 4.89 (m, 1H), 6.9 (m, 1H), 7.14 (m, 1H), 7.21 (m, 3H), 7.32 (t, 1H), 7.42 (t, 1H), 7.56 (m, 31H), 7.79 (d, 1H), 9.88 (br s, 1H), 10.08 (br s, 1H); Mass Spectrum: M+H+ 533.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29]CC=C)=[O:28])=[CH:5][CH:4]=1)#[N:2].N1CCOCC1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)CC1c1ccc(C#N)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of allyl 4-(4-cyanophenyl)-2-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydro-3-pyridinecarboxylate (Example 46) (1.00 g, 2.27 mmol) and tetrakis(triphenylphosphin)-palladium(0) (68 mg, 0.059 mmol) in tetrahydrofuran (50 ml) is slowly added morpholine (3.36 g, 38.6 mmol). After stirring at room temperature for 1 h, the reaction mixture is quenched with water (50 ml). The basic solution (pH ca. 10) is neutralised with 1 N hydrochloric acid, and the aqueous phase is extracted with ethyl acetate (2×100 ml). The combined organic layers are washed with water, dried, and the solvent is removed in vacuo to yield pure product.
Reaction SMILES: Cl[C:2]1[C:3]([N+:30]([O-:32])=[O:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6].[CH3:33][NH:34][CH3:35].O>CN(C=O)C>[CH3:33][N:34]([CH3:35])[C:2]1[C:3]([N+:30]([O-:32])=[O:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6]
Reactant: CNC
Reactant: O=C(NC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cccc(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Step 2): A solution of 3-chloro-2-nitro-N-(1-diphenylmethylpiperidin-4-yl)benzamide (13.5 g, 30 mmol) and 40% dimethylamine (20 ml) in DMF (60 ml) was heated at 130° C. for 15.5 hours in a sealed tube. The mixture was poured into water and extracted with ether. The organic layer was washed with water, dried (MgSO4) and concentrated. The residue was recrystallized (ethyl acetate/hexane) to give 3-dimethylamino-2-nitro-N-(1-diphenylmethyl piperidin-4-yl)benzamide (88.5%): mp 176° C.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][N:17](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([CH:47]([CH3:49])[CH3:48])[CH2:42]1)=[O:40])=[O:4].[OH-].[K+]>CO.CN(C)C=O>[CH3:50][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[CH:7][C:6]=1[NH:38][C:39]([CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([CH:47]([CH3:48])[CH3:49])[CH2:42]1)=[O:40])=[O:4]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)C4CCCN(C(C)C)C4)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)C4CCCN(C(C)C)C4)c(C(=O)N(C)C)c3)cc12
Reaction time: 1 h
Yield: 31.6 %

Procedure:
1-iso-Propyl-piperidine-3-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (185.1 mg, 0.27 mmol) was dissolved in methanol (0.5 mL) and dimethylformamide (0.5 mL), cooled to 0° C. and 50% w/v aqueous potassium hydroxide (0.2 mL) was added. After 1 hour, the reaction was quenched by addition of concentrated hydrochloric acid (0.2 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 1-isopropyl-piperidine-3-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-amide (46.0 mg, 31.9%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 0.98 (d, J=6.5 Hz, 6H), 1.59 (m, 2H), 1.76 (m, 2H), 2.16 m, 3H, 2.32 (m, 2H), 2.70 (m, 1H, 2.87 (s, 3H), 2.97 (s, 3H, 3.82 (s, 3H), 7.04 (t, J=7.5 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.28 (dt, J=1.5, J=7.5 Hz 1H), 7.61 (dd, J=1.5 Hz, J=7.5 Hz, 1H), 7.59-7.61 (m, 2H), 7.65 (d, J=8.0 Hz, 1H), 7.72-7.74 (m, 2H), 8.54 (d, J=2.5 Hz, 1H), 9.51 (s, 1H), 11.92 (s, 1H). MS: m/z 541 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:18]=[CH:17][C:16](Br)=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)=[O:5].[N:20]1([CH2:26][C:27]2[S:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[N:18]=[CH:17][C:16]([C:30]2[S:31][C:27]([CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:28][CH:29]=2)=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)=[O:5]
Reactant: Cc1cc(NC(=O)c2cc(Br)cnc2N)cc(C)n1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Product: Cc1cc(NC(=O)c2cc(-c3ccc(CN4CCOCC4)s3)cnc2N)cc(C)n1

Procedure:
Reaction of 2-amino-5-bromo-N-(2,6-dimethyl-pyridin-4-yl)-nicotinamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A26”; HPLC/MS: 1.09 min, [M+H]=424;
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[C:6]([O:16][CH3:17])(=[O:15])/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]([O:13]C)=O>C1COCC1>[CH:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:13])[CH:7]1[C:6]([O:16][CH3:17])=[O:15])([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: COC(=O)/C=C/CCC(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)CCC1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
An isopropylmagnesium bromide (58 mL, 58 mmol) solution (15% in THF, ˜1 M) was treated with Cu(I)I (0.28 g, 1.5 mmol) and cooled to 0° C. A solution of (E)-dimethyl hex-2-enedioate (5.0 g, 29 mmol; See Example 80, Step 1) was added dropwise, and the solution was stirred at 0° C. for an additional 30 minutes and then at room temperature. The product was poured into saturated NHCl4 (250 mL) with rapid stirring. The mixture was extracted into DCM. The combined organics were back extracted with H2O, and dried with MgSO4, filtered, and concentrated under reduced pressure to yield methyl 2-isopropyl-5-oxocyclopentanecarboxylate (5.4 g, 100%), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.76-3.73 (m, 3H), 2.94-2.91 (m, 1H), 2.48-2.16 (m, 2H), 1.87-1.84 (m, 2H), 1.68-1.43 (m, 2H), 0.97-0.84 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:7]=2[N:8]=1.[Al].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:11]1[C:10]([CH3:13])=[N:9][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1
Reactant: CNc1ncc2ccc(C)nc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CC#N
Product: CNc1ncc2cc(Br)c(C)nc2n1
Yield: 30.7 %

Procedure:
Cool a solution of N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine (6.73 g, 38.6 mmol) in acetonitrile (160 mL) in an ice bath and shield from light with aluminum foil. Add N-bromosuccinimide (6.88 g, 38.6 mmol) and stir at 0° C. for 2 h. Transfer the reaction to a 5° C. refrigerator for 4 days. Collect the solid by filtration. Wash the solid with DCM and concentrate the washings to obtain the title compound (3.0 g, 31% yield). MS (m/z): 253.0/255.0 (M+1).
Reaction SMILES: [H-].[Na+].CO[C:5]([C:7]1[C:16]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[C:9]([O:31][CH3:32])[C:8]=1[CH2:33][C:34](=[O:44])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:6]>CN(C=O)C.C(OCC)C>[CH:18]([O:17][C:16]1[C:7]2[C:5](=[O:6])[N:35]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:34](=[O:44])[CH2:33][C:8]=2[C:9]([O:31][CH3:32])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1c(CC(=O)NCc2ccc(F)cc2)c(OC)c2cccnc2c1OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A 60% sodium hydride (NaH) mineral oil dispersion (0.002 g, 0.06 mmol was added to a solution of 8-benzhydryloxy-6-[(4-fluoro-benzylcarbamoyl)-methyl]-5-methoxy-quinoline-7-carboxylic acid methyl ester (0.020 g, 0.04 mmol) in 1 mL of anhydrous DMF. The resulting indigo-tinted solution was stirred at rt for a period of 30 min, and then diluted with diethyl ether (50 ml) and washed with sat. aq. NH4Cl (25 mL). The organic layer was dried over Na2SO4 and solvent was removed by rotary evaporation. The residue was purified by silica gel chromatography (1/1 hexanes/diethyl ether and then 100% MeOH to elute product fractions) to give 9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6,8-dione 295 (9 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[C:4]([N:6]([CH2:11][C:12]1[N:13]=[N:14][C:15]([NH:21][NH2:22])=[CH:16][C:17]=1[CH2:18][CH2:19][CH3:20])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].[CH:28](O)=O>>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[C:4]([N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:11][C:12]1[C:17]([CH2:18][CH2:19][CH3:20])=[CH:16][C:15]2[N:14]([CH:28]=[N:22][N:21]=2)[N:13]=1)=[O:5]
Reactant: CCCc1cc(NN)nnc1CN(CC(C)C)C(=O)c1cc(F)ccc1F
Reactant: O=CO
Product: CCCc1cc2nncn2nc1CN(CC(C)C)C(=O)c1cc(F)ccc1F

Procedure:
A solution of 2,5-difluoro-N-(6-hydrazino-4-propyl-pyridazin-3-ylmethyl)-N-isobutyl-benzamide (78 mg, 0.21 mmol) in HCOOH (3 ml) is heated at 110° C. overnight. The solvent is removed in vacuo and to the residue is added EtOAc (10 ml) and saturated NaHCO3 aqueous solution (10 ml). The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. Preparative TLC separation of the residue with 5% MeOH in CH2Cl2 provides the title compound as a light yellow oil. 1H NMR (CDCl3) (mixture of rotamers) 9.07 (s, 0.2H), 9.00 (s, 0.8H), 7.87 (s, 0.8H), 7.78 (s, 0.2H), 6.96-7.13 (m, 3H), 4.91 (s, 1.6H), 4.62 (s, 0.4H), 3.13 (d, 2H), 2.71 (t, 1.6H), 2.40 (t, 0.4H), 2.09-2.13 (m, 0.2H), 1.92-2.00 (m, 0.8H) 1.74-1.83 (m, 1.6H), 1.48-1.55 (m, 0.4H), 1.09 (t, 2.4H), 1.00 (d, 1.2 H), 0.96 (t, 0.6H), 0.81 (d, 4.8H).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([CH:14]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH2:26])([C:10]([O:12]C)=O)[C:6]([O:8][CH3:9])=[O:7].CN(C)C=O.Cl>CO>[CH3:9][O:8][C:6]([C:5]1([CH3:4])[CH:14]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[CH:18][C:17]=2[NH:26][C:10]1=[O:12])=[O:7]
Reactant: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C1(C)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccc(OC)cc1
Yield: 88.3 %

Procedure:
A 25% (by weight) sodium methoxide in methanol solution (14.2 ml; 625 mmole; 4.6 eq.; d=0.945) and α-methyl-[2-(2-amino-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (5.96 g; 13.56 mmole) in methanol (30 ml) and dry dimethylformamide (35 ml) were refluxed (~95° C.) overnight. 1N Hydrochloric acid was added with stirring producing a white precipitate that was collected by suction-filtration, washed with water (three times) and dried in vacuo giving 4.88 g of a white solid which contained an impurity as shown by NMR. The impurity disappeared after the sample stood overnight.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:17]=1)=[N:7][C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[CH:9][N:10]=2.[NH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:22]=2[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[O:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:7]=[C:6]3[N:17]=[C:2]([C:25]4[CH:26]=[CH:27][C:21]5[O:20][C:19]([NH2:18])=[N:23][C:22]=5[CH:24]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Reactant: Clc1ccc2ncc(N3CCOCC3)nc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc2cc(-c3ccc4ncc(N5CCOCC5)nc4n3)ccc2o1
Yield: 71.8 %

Procedure:
A mixture of 6-chloro-3-morpholinopyrido[2,3-b]pyrazine (E-29) (100 mg, 0.4 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (108 mg, 0.6 mmol, 1.5 eq), Pd(PPh3)4 (50 mg, 0.04 mmol, 0.1 eq), and Na2CO3 (0.22 g, 2.0 mmol, 5.0 eq),) were dissolved in a mixture of 1,4-dioxane (15 mL) and water (5 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux temperature for 2 h. The reaction was complete based on TLC analysis. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (60:1:0.02 MeOH-DCM-NH3.H2O) to afford 5-(3-morpholinopyrido[2,3-b]pyrazin-6-yl)benzo[d]oxazol-2-amine (2) (100 mg, 72% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 8.86 (s, 1H), 8.26 (m, 1H), 8.06 (m, 2H), 7.92 (m, 1H), 7.55 (bs, 2H), 7.47 (m, 1H), 3.82 (m, 8H); ESI-MS m/z: 349.14 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br-:8].[Br:9][CH2:10][CH2:11][CH2:12][N+:13]([CH2:20][CH2:21][CH3:22])([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].CN(C=O)C>C(OCC)C>[Br-:9].[Br-:8].[CH2:17]([N+:13]([CH2:12][CH2:11][CH3:10])([CH2:14][CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:18][CH3:19]
Reactant: CCC[N+](CCC)(CCC)CCCBr
Reactant: Cc1ccncc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC[N+](CCC)(CCC)CCC[n+]1ccc(C)cc1
Yield: 38.1 %

Procedure:
4-Methylpyridine (307 mg, 3.3 mmol), (3-bromopropyl)tripropylammonium bromide (1.0 g, 2.9 mmol), and 4 mL DMF were stirred at 100° C. in a pressure vessel for 14 h. After cooling down, the reaction mixture was added dropwise to a vigorously stirred diethyl ether (100 mL). The oily precipitates formed was collected and further purified by column chromatography (SiO2, gradient from 1:4 to 1:1 MeOH/CH2Cl2) to furnish 1-(3-tripropylammoniopropyl)-4-methylpyridinium dibromide as a colorless solid (484 mg, 38%). 1H NMR (400 MHz, CD3OD): δ 1.03 (t, J=7.0 Hz, 9 H), 1.77 (m, 6 H), 2.51 (m, 2 H), 2.70 (s, 3 H), 3.28 (m, 6 H), 3.49 (m, 2 H), 4.72 (t, J=7.8 Hz, 2 H), 7.99 (d, J=6.4 Hz, 2 H), 8.99 (d, J=6.4 Hz, 2 H); HRMS (FAB+): m/z=357.1906 [M-Br]+ (calcd for C18H34BrN2: 357.1900).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:25]=[C:26]([O:28][C@@H:29]([CH3:39])[CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH:27]=3)[C:17]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>CO.Cl>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:25]=[C:26]([O:28][C@@H:29]([CH3:39])[CH2:30][OH:31])[CH:27]=3)[C:17]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2nccs2)c1
Agent: Cl
Solvent: CO
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
A mixture of 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide (0.15 g, 0.33 mmol) in methanol (10 mL) and 1M hydrochloric acid (10 mL) was stirred for 90 mins at RT. The volatiles were removed in vacuo and the residue taken to pH6 with saturated aqueous sodium bicarbonate solution then extracted into ethyl acetate (3×30 mL) and the combined organic layers washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvents removed in vacuo to a residue which was chromatographed on silica eluting with a gradient of 0-10% methanol in ethyl acetate to give the desired compound (65 mg).