Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)no1
Temperature: 50 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (5.0 g, 34.9 mmol), benzyl bromide (6.84 g, 40 mmol) and potassium carbonate (8.3 g, 60 mmol) in N,N-dimethylformamide (100 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 95:5 to 50:50). Solvent was removed to obtain a solid (1.68 g, 21%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:24])(=[O:23])[N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)CC1
Yield: 54.6 %

Procedure:
Using general procedure A, 1-Boc-4-piperidone (1.00 g, 5.03 mmol) and 4-amino-N,N-dibenzyl-benzenesulfonamide (Mikhura, I. V.; et al., Russ. J. Org. Chem., 36, 1, 2002, 64-68) (1.53 g, 4.34 mmol) afforded 4-(4-dibenzylsulfamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.27 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:29]3[CH:34]=[N:33][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:31][CH:30]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)c1
Yield: 48 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]-morpholine as in General Procedure 4A to give the title compound as an off-white solid (48% yield). M.p. 206-207° C., LCMS: m/z=423.99 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.53 (m, 6H), 3.60-3.67 (m, 2H), 3.80-3.87 (m, 4H), 4.48 (s, 2H), 4.86 (s, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.66 (s, 1H), 6.89-7.06 (m, 3H), 7.55 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H).
Reaction SMILES: F[CH:2]1[CH:8](N)[CH2:7][CH2:6][CH2:5][N:4]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[N+:15]([O-:17])=[O:16])C1.ClC1NN=CC=1[N+]([O-])=[O:25].O.Cl.N1CCC(=O)CC1.[F-].[K+]>CS(C)=O>[N+:15]([C:11]1[CH:12]=[N:13][NH:14][C:10]=1[N:4]1[CH2:5][CH2:6][C:7](=[O:25])[CH2:8][CH2:2]1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cn[nH]c1Cl
Reactant: NC1CCCN(c2[nH]ncc2[N+](=O)[O-])CC1F
Agent: Cl
Agent: O=C1CCNCC1
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCN(c2[nH]ncc2[N+](=O)[O-])CC1

Procedure:
FIG. 10 shows an exemplary synthesis of 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 52 from 5-chloro-4-nitro-1H-pyrazole 3. Heating 3 with piperidin-4-one hydrochloride hydrate and potassium fluoride in a suitable solvent such as dimethylsulfoxide or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 46. Heating 46 with trimethylsilyl chloride and triethylamine in a suitable solvent such as DMF or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine 47. Fluorination of 47 using SelectFluor® in acetonitrile at a suitable temperature or using methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 48. Ring expansion of 48 to ethyl 6-fluoro-1-(4-nitro-1H-pyrazol-5-yl)-5-oxoazepane-4-carboxylate 49 may be achieved using ethyl diazoacetate and boron trifluoride diethyl etherate in a suitable solvent such as dichloromethane at suitable temperatures or using methods described in the literature. Decarboxylation of 49 by heating with hydrochloric acid at a suitable temperature or by methods described in the literature to give 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-one 50. Reductive amination of 50 by methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 51. The amine of 51 can be protected with a suitable protecting group such as trifluoroacetamide using trifluoroacetic anhydride with diisopropylethylamine in a suitable solvent such as dichloromethane, or using other methods described in the literature, to give amine-protected 52.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[C:10]=2[F:34])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:34][C:10]1[C:11]([CH2:24][NH:25][CH3:26])=[CH:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)(=[O:16])=[O:15])[C:9]=1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-4-fluoro-1-[(3-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (445 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 281 mg, 73%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18]>[Ni].[Pd]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18]
Reactant: CSCCC(N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Pd]
Product: CSCCC(NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and DL-methionine using Raney nickel or palladium/activated carbon (10%) as a catalyst. The compound had a melting point of 245° C. (decomposition) and an RF -value of 0.71 (determined as indicated in Example K).
Reaction SMILES: [CH2:1]([N:8]([CH3:13])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:28][C:29]1[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O.O.O.O.O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[I-].[Na+]>CN(C)C=O>[CH2:14]([O:28][C:29]1[O:33][C:32]([C:34]([O:36][CH2:10][C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:13])=[O:12])=[O:35])=[CH:31][CH:30]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CN(Cc1ccccc1)C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC(=O)N(C)Cc2ccccc2)o1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
The above prepared N-benzyl-2-chloro-N-methylacetamide (0.250 g) was dissolved in 10 mL of N,N-dimethylformamide. To this solution were added 5-(tetradecyloxy)furan-2-carboxylic acid (0.180 g, 0.544 mmol), tetrabutylammonium hydroxide pentahydrate (0.209 g, 0.554 mmol), and sodium iodide (˜15 mg). The suspension was heated to 60° C. with stirring for 14 hrs. The reaction was quenched with brine (5 mL), water (5 mL) and EtOAc (40 mL). The phases were separated and the organic phase was further diluted with EtOAc (30 mL), washed successively with water (30 mL) and brine (30 mL) and then dried and concentrated. The resulting crude material was purified by flash chromatography eluting with 5-20% EtOAc in hexanes to give the desired compound as a viscous oil. The material was further purified by recrystallization from 2-propanol and water to yield 0.130 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 7.20-7.40 (m, 6H), 5.30-5.35 (m, 1H), 4.92 (s, 2H), 4.50-4.61 (app d, 2H), 4.10 (m, 2H), 2.90-2.98 (app d, 3H), 1.79 (p, 2H), 1.18-1.50 (m, 22H), 0.89 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1.Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)Cn1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Agent: Br
Product: CCOC(=O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
1.8 g (5.05 mmol) of ethyl {4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetate and 1.9 g (7.6 mmol) of 4-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 0.45 g (20% of theory)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].I[CH3:17]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:15][CH3:17])([CH3:14])[CH3:13])[CH:7]=1)[CH3:4]
Reactant: CCOc1cccc(C(C)(C)O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1cccc(C(C)(C)OC)c1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Sodium hydride (3.261 g, 81.54 mmol, 60% in mineral oil, Aldrich) was washed twice with hexane, and tetrahydrofuran (60 mL) was added. To this suspension was added 2-(3-ethoxy-phenyl)-propan-2-ol (4.9 g, 27.18 mmol). The mixture was stirred at 45° C. for 1.5 h until the bubbling subsided. It was cooled down to 0° C. and iodomethane (5.08 mL, 81.54 mmol, Aldrich) was added. After 4 h of stirring at room temperature, another portion of iodomethane (5.08 mL, 81.54 mmol) was added. The mixture was stirred at room temperature for 4 d then quenched at 0° C. with cold 20% solution of ammonium chloride. The product was extracted with ethyl acetate (2×1 L). The organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 1-ethoxy-3-(1-methoxy-1-methyl-ethyl)-benzene (5.15 g, 97%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:29]([CH3:30])=[CH:28][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22](C)[C:21](=[O:27])[CH2:20]4)[S:16][C:12]=2[C:11]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C=C2C(=CC=1)NC(=O)C2>>[C:1]([O:5][C@@H:6]([C:10]1[C:29]([CH3:30])=[CH:28][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:27])[CH2:20]4)[S:16][C:12]=2[C:11]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3ccc4c(c3)CC(=O)N4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: O=C1Cc2cc(Br)ccc2N1
Product: Cc1cc2nc(-c3ccc4c(c3)CC(=O)N4)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-oxoindolin-5-yl)benzo[d]thiazol-6-yl)acetic acid was prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxoindolin-5-yl)benzo[d]thiazol-6-yl)acetic acid except 5-bromoindolin-2-one was used instead of 5-bromo-1-methylindolin-2-one. LCMS-ESI+: calc'd C28H26ClN2O4S: 521.1 (M+H+); Found: 521.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 7.91-7.88 (m, 2 H), 7.77 (s, 1H), 7.66 (m, 1H), 7.59-7.56 (m, 2H), 6.99 (d, 1H), 5.23 (s, 1H), 3.61 (s, 2H), 2.63 (s, 3H), 2.59 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([S:10]([C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:17]2[CH:18]=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:16]=2[F:15])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH3:14]
Reactant: CCS(=O)(=O)c1ccc(Br)c(C#N)c1
Reactant: COc1ccc(COc2ccc(F)c(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(OCc3ccc(OC)cc3)ccc2F)c(C#N)c1
Temperature: 110 °C
Yield: 51 %

Procedure:
To 2-bromo-5-(ethylsulfonyl)benzonitrile (Preparation 75, 1.09 g, 3.96 mmol) in dioxane/water (5:1 v/v, 66 mL) was added 2-(2-fluoro-5-((4-methoxybenzyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 71, 1.56 g, 4.35 mmol) and sodium carbonate (1.26 g, 11.9 mmol). The reaction mixture was degassed and tetrakis(triphenylphosphine) palladium(0) (462 mg, 0.40 mmol) was added, and the reaction heated to 110° C. under nitrogen for 12 hours. After cooling to room temperature, silica gel was added, and the solvent removed under reduced pressure. The residue was purified using silica gel column chromatography eluting with EtOAc/cyclohexane 1:3 followed by reverse phase column chromatography eluting with MeCN/water, with 0.1% NH3 0-100% to afford the title compound as a solid in 51% yield, 851 mg.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][NH:12][CH3:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].F[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)[CH:28]=[CH:27][N:26]=2)=[C:17]([O:41][CH3:42])[CH:16]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[CH3:42][O:41][C:17]1[C:18]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)[CH:28]=[CH:27][N:26]=2)=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([N:12]([CH3:13])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH:16]=1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(N(C)CCN(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
tert-Butyl N-methyl-N-(2-methylaminoethyl)carbamate (Intermediate 173, 300 mg, 1.59 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methy-lindol-3-yl)pyrimidin-2-amine (Intermediate 129, 522 mg, 1.33 mmol) and DIPEA (0.462 mL, 2.65 mmol) in DMA (5 mL). The mixture was heated in a microwave at 100° C. for 4 h. The mixture was then diluted with EtOAc and washed with water (5×), brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-2% CH3OH in CH2Cl2 gave the title compound (431 mg, 58%) as an orange solid after trituration with iii diethyl ether; 1H NMR: 1.37 (9H, s), 2.79 (3H, s), 2.88 (3H, s), 3.29-3.36 (2H, m), 3.39-3.44 (2H, m), 3.89 (3H, s), 3.99 (3H, s), 6.85 (1H, d), 7.14 (1H, t), 7.21-7.28 (2H, m), 7.53 (1H, br d), 8.04 (1H, s), 8.31-8.38 (3H, m), 8.72 (1H, br s); m/z: ES+ MH+ 562.35.
Reaction SMILES: C([O:4][CH:5]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]2=[N:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH:6]1[O:38]C(=O)C)(=O)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:4][CH:5]1[CH2:26][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]2=[N:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=[C:7]2[CH:6]1[OH:38]
Reactant: CCOC(=O)CCCCCCN1CC(OC(C)=O)C(OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCN1CC(O)C(O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-5-(7-ethoxy-7-oxoheptyl)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7,8-diyl diacetate (step 1) (30 mg, 0.054 mmol) in THF (3 ml) and water (1.0 ml) was added LiOH (7.70 mg, 0.322 mmol). The suspension was heated to reflux for 1 hour and allowed to stand at RT overnight. The mixture was again heated at reflux for 30 minutes and after cooling to RT, 1M HCl was added to adjust the pH to below pH 5. The volatile solvent was evaporated and the resulting mixture was extracted with EtOAc (10 ml). The organic extract was washed with water, dried over MgSO4, filtered and concentrated in vacuo to afford a mixture of the title products;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[CH:6]=[N:7]\[OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[OH:8]/[N:7]=[C:6](\[Cl:11])/[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O/N=C\c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of (E)- and/or (Z)-4-chloro-benzaldehyde oxime (27.0 g, 173 mmol) in DMF (173 mL) was added N-chlorosuccinimide (22.8 g, 173 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (28.4 g, 86%) which was obtained as a light yellow solid. MS: m/e=189.1 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH2:30][CH3:31])[C:21]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]#[C:26][CH3:27])=[O:22].O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:20]([CH2:30][CH3:31])[C:21]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]#[C:26][CH3:27])=[O:22])=[CH:7][CH:6]=2
Reactant: Oc1ccc2ncc(Br)cc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a stirred mixture of 3-bromo-6-hydroxyquinoline (0.179 g) and anhydrous potassium carbonate (0.121 g) in dry N,N-dimethylformamide (2 ml) at 80° C. was added 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide (0.197 g) and the reaction maintained at this temperature for 15 hours. The brown suspension produced was cooled to ambient temperature, poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulphate then evaporated under reduced pressure to give a brown gum. The gum was fractionated by chromatography (silica; hexane/ethyl acetate) to give 2-(3-bromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide (0.125 g) as a colourless solid, m.p. 109–112° C., 1H NMR (CDCl3) δ: 1.08(3H, t); 1.58 (3H, s); 1.59(3H, s); 1.77(3H, s); 1.99–2.06(2H, m); 4.54(1H, t); 6.37(1H, s); 7.02(1H, m); 7.42(1H, dd); 8.02(1H, d); 8.19(1H, m); 8.78(1H,m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4c(ccn4C)c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (400 mg, 1.24 mmol), (prepared as described for the starting material in Example 9), potassium carbonate (500 mg, 3.62 mmol), 5-hydroxy-1-methylindole (231 mg, 1.57 mmol), (prepared as described for the starting material in Example 291), and DMA (5.0 ml) for 5 minutes. The mixture was then stirred at 90° C. for 3 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography, gradient elution, with dichloromethane/methanolic ammonia (7M), (100/0 to 90/10) to give 6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (247 mg, 44%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[N:17][CH:18](Br)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:25]>CCOCC>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[N:17][CH:18]([NH2:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)N=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Solvent: CCOCC
Product: CCOC(=O)C(N)N=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.1 parts of ethyl (2-benzoyl-4-chlorophenylazo)bromoacetate in 16 volume parts of ether is added 160 volume parts of concentrated aqueous ammonia. After stirring the mixture for 1 hour at room temperature, the ether layer is separated, washed with water and evaporated to remove the solvent. The crystalline residue is collected by filtration, washed with ethanol and dried. The procedure gives ethyl (2-benzoyl-4-chlorophenylazo)-aminoacetate. Recrystallization from ethanol gives yellowish orange needles melting at 126°-127°C.