Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][OH:18].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]([O:18][CH2:17][C:5]1[N:4]([CH2:3][C:2]([F:1])([CH3:20])[CH3:19])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(F)Cn1c(CO)nc2cnc3cccnc3c21
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1nc2cnc3cccnc3c2n1CC(C)(C)F
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol (1.53 g, 5.58 mmol) dissolved in 50 mL of CH2Cl2 was treated with triethylamine (1.55 mL, 11.2 mmol), acetic anhydride (663 μL; 6.70 mmol), and 10 mg of 4-(dimethylamino)pyridine (DMAP). After stirring for 2 hours, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed successively with 3.5% NaH2PO4 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 40-60% acetone/hexanes) gave 1.59 g of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate as an off-white powder.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26]O)[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7].[CH:33]([N:36](C(C)C)[CH2:37]C)(C)C.CNC>C1COCC1>[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26][N:36]([CH3:37])[CH3:33])[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Methanesulfonyl chloride (18 μL, 0.24 mmol) was added to a solution of Compound 133 (46 mg, 0.12 mmol) and diisopropylethylamine (43 μL, 0.25 mmol) in THF (1 mL) at 0° C. After stirring for 3 h, dimethylamine (2M, 1 mL, 2 mmol) was added, and the reaction stirred for 16 h. The solution was concentrated in vacuo and purified by prep-HPLC to give 32 mg (65%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CD3OD) δ 8.36 (br s, 1H), 8.22 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.05 (d, 1H, J=7.6 Hz), 7.88-7.94 (m, 2H), 7.85 (s, 1H), 7.44 (s, 1H), 4.57 (s, 2H), 3.33 (q, 2H, J=7.2 Hz), 2.94 (s, 6H), 2.39 (s, 3H), 1.30 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C23H25N3O2S, 408; found 408.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.C([O:21]B(OC(C)C)OC(C)C)(C)C.C(O)(=O)C.OO>C1COCC1>[C:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([OH:21])=[CH:8][CH:9]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: OO
Agent: [Li]C(C)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Sec-butyllithium (53.2 mmoles, 41 ml of 1.3M in hexane) was added dropwise at -78° C. to 4-bromo-t-butoxybenzene (53.2 mmoles, 12.2 g) in 200 ml THF, stirred at -78° C. for 1 hour, and added slowly to a solution of triisopropylborate (58.5 mmoles, 11.0 g) in 50 ml THF while maintaining the temperature below -60° C. The mixture was allowed to warm gradually to -20° C. Chilled acetic acid (80 mmoles,9.6 ml) was added. Hydrogen peroxide (58.5 mmoles, 5.9 ml of 30% diluted with 5 ml water) was added dropwise over 15 minutes while maintaining the temperature below 0° C. After stirring 10 minutes, the solution was washed with ammonium sulfate solution, dried, and concentrated. The residue was triturated with hexane and filtered to yield 4.2 g of 4-t-butoxyphenol. (MS).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([CH2:8][CH2:9][C:10]2[C:11]([CH3:33])=[N:12][O:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:7])[CH2:3][CH2:2]1.I[CH3:35]>>[CH:1]1([CH2:4][N:5]([CH3:35])[C:6]([CH2:8][CH2:9][C:10]2[C:11]([CH3:33])=[N:12][O:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)NCC1CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)N(C)CC1CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-(4′-{4-[2-(cyclopropylmethyl-carbamoyl)-ethyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and iodomethane.
Reaction SMILES: [CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[CH3:33]/[C:34](=[CH:40]\[C@@H:41]([N:45]([CH3:54])[C:46](=[O:53])[C@H:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[NH2:48])[CH:42]([CH3:44])[CH3:43])/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([NH:48][C@@H:47]([C:49]([CH3:52])([CH3:50])[CH3:51])[C:46]([N:45]([CH3:54])[C@@H:41]([CH:42]([CH3:43])[CH3:44])/[CH:40]=[C:34](\[CH3:33])/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:53])=[O:5]
Reactant: C[C@H](C(=O)O)C(C)(C)c1ccccc1
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a cooled (0° C., ice bath) solution of (2S)-2,3-dimethyl-3-phenylbutanoic acid (0.11 g, 0.57 mmol, from Reference Example 25), hydroxybenzotriazole (93 mg, 0.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (0.15 g, 0.80 mmol) in anhydous dimethylformamide (2 ml) is added N-methylmorpholine (95 uL, 0.86 mmol) via syringe under an inert atmosphere. After stirring for 15 minutes at 0° C., the cooling bath is removed, and the resulting mixture is stirred for 1 hour. The solution is cooled at 0° C. (ice water bath), and to this mixture is added a solution of ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate hydrochloride (0.56 mmol) in anhydrous dimethylformamide (2 ml). The cooling bath is removed, and the resulting mixture is stirred for 22 hours at room temperature under an inert atmosphere. The mixture is diluted with water, and the aqueous layer is extracted with ethyl acetate (3 times). The combined extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed (silica gel, flash column), to provide a white foam (0.20 g, 71%). MS (ES+): (M+H)=487.0
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[S:22][N:21]=4)[CH:18]=3)[N:13]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:35])=[O:34])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nsc(N)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a mixture of tert-butyl (3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.35 g, 0.577 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. The reaction was stirred for 2 h at RT. The solvent was then removed in vacuo and the residue was triturated with Et2O to give 3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-amine (0.25 g, 85.6%). MS (ESI, pos. ion) m/z: 506.1 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH2:19][OH:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[CH:44][C:45]=1[F:46]>>[F:39][C:40]1[CH:41]=[C:42]([CH:43]=[CH:44][C:45]=1[F:46])[O:20][CH2:19][C:16]1[CH2:17][S:18][C@@H:13]2[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:37](=[O:38])[N:14]2[C:15]=1[C:21]([O:23][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:22]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: Oc1ccc(F)c(F)c1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(F)c(F)c3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 7-phenoxyacetamido-3-hydroxymethyl-3-cephem-4-carboxylate and 3,4-difluorophenol, to afford 326 mg of the title compound as a powder.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH:20][CH2:21][CH2:22][CH3:23])[CH:17]([CH3:19])[CH3:18]>C(O)C>[CH2:16]([N:20]([CH2:21][CH2:22][CH3:23])[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH:17]([CH3:19])[CH3:18]
Reactant: CCCNCC(C)C
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 92.7 %

Procedure:
To a solution of ethyl 4-fluoro-3-nitrobenzoate (7.4 g, 0.035 mol) in ethanol (100 mL) was added N-isobutyl-N-propylamine (11.98 g, 0.104 mol) at RT. The reaction mixture was heated at 60° C. for 12 h. It was then concentrated under reduced pressure. The residue was dissolved in water (40 mL) and was acidified to pH=4 with 1 M HCl solution. It was extracted with EtOAc (2×75 mL). The combined organic phases were washed with brine, dried over sodium sulphate and evaporated to afford the title compound (10 g, 93%) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.92 (m, 1H), 7.38 (m, 1H), 4.28 (m, 2H), 3.15 (m, 2H), 3.03 (m, 2H), 1.86 (m, 1H), 1.51 (m, 2H) 1.28 (m, 3H), 0.78 (m, 9H). LC/MS (Method A): 309.0 (M+H)+. HPLC (Method B) Rt 5.05 min (purity: 99.4%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=1.[CH3:12][NH2:13]>O>[CH3:8][C:6]1[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=[C:2]([NH:13][CH3:12])[N:7]=1
Reactant: CN
Reactant: Cc1nc(Cl)cc2cnnn12
Solvent: O
Product: CNc1cc2cnnn2c(C)n1

Procedure:
To a stirred solution of 3.4 g (20 mmole) of 5-chloro-7-methyltriazolo[1,5-c]pyrimidine in 50 ml of water was added 1.25 g (40 mmole) of methylamine as a 40% aqueous solution. The mixture was heated in an oil bath and thickened rapidly as a result. The solid was separated by filtration, and was then recrystallized from a benzene-hexane mixture with treatment with decolorizing charcoal. The product was white needles of 7-methyl-5-(N-methylamino)triazolo[1,5-c]pyrimidine, m.p. 162°-164° C. Analysis: Calculated for C7H9N5 : %C, 51.5; %H, 5.6; %N, 42.9; Found: %C, 51.6; %H, 5.4; %N, 43.1.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Br[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[C:36]#[N:37]>>[CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20]([C:34]4[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=4[C:36]#[N:37])[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: N#Cc1ccccc1Br
Reactant: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(B4OC(C)(C)C(C)(C)O4)CC3)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(c4ccccc4C#N)CC3)cc2)C1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH:31]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: COC(=O)CCCC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 5-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-5-phenylpentanoate (0.13 g, 0.22 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.018 g, 0.44 mmol) in water (1 mL). After stirring at room temperature for 24 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.075 g, 56%); 1H NMR (DMSO-d6): δ 1.41-1.58 (m, 4H), 1.81 (t, 2H, J=6.8 Hz), 1.97-2.11 (m, 2H), 2.26-2.35 (m, 4H), 2.49-2.53 (m, 2H), 2.61-2.67 (m, 5H), 3.84 (t, 2H, J=6.8 Hz), 4.26 (d, 1H, J=5.6 Hz), 4.74 (d, 1H, J=5.6 Hz), 5.15-5.19 (m, 1H), 6.76 (t, 1H, J=6.8 Hz), 6.86 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.17-7.24 (m, 3H), 7.29-7.32 (m, 1H), 7.35-7.38 (m, 3H), 10.80 (s, 1H), 12.07 (br, 1H); MS for C34H39N5O4 m/z 582.12 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([NH:9][C:10]2=O)[CH2:7]3)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[Cl:16])[CH2:7]3)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NC2CC(C2)c2ccc(Br)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: ClC1=NC2CC(C2)c2ccc(Br)cc21
Temperature: 85 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask was placed 5-bromo-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one (223 g, 884.55 mmol, 1.00 equiv), PhCH3 (3500 mL), PCl5 (560 g, 2.69 mol, 3.00 equiv), and DIPEA (275 g, 3.00 equiv). The resulting solution was stirred at 85° C. for 5 h and quenched by the addition of 300 g of DIPEA. The solids were filtered out and the filtrate was concentrated under vacuum to afford 260 g (crude) of 5-bromo-8-chloro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene as a black oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[C:19]([OH:20])=[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24]([OH:25])=[N:11][C:6]=21
Reactant: Nc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2c3ccc(Br)cc3nn2c(O)c1-c1ccccc1
Yield: 97.4 %

Procedure:
9.9 g (46.7 mmol) 6-Bromo-1H-indazol-3-ylamine, 11 g (46.7 mmol) diethyl phenylmalonate and 19.8 mL (83.1 mmol) tributyl amine were heated for 15 h at 180° C. The reaction mixture was treated with 2M sodium hydroxide and water and extracted three times with tert-butyl methyl ether. The organic phase was discarded and the aqueous phase was acidified with conc. hydrochloric acid. The precipitate was collected by filtration and washed with water to obtain the desired product (16.2 g) which was however contaminated and which was used in the next step without further purification.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:23])[CH:15]=1.[OH-].[NH4+]>ClCCl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:3])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1ccc(Br)cc1F
Reaction time: 0.33 h

Procedure:
At 0° C., 1,1′-carbonyldiimidazole (8.8 g, 54.3 mmol) was added in portions to a stirred mixture of 4-bromo-2-fluorobenzoic acid (6 g, 27.3 mmol) in dichloromethane (100 ml). After 20 minutes, a clear solution was obtained. Ammonium hydroxide (28%, 30 ml) was added and the mixture was stirred overnight. Aqueous layer was isolated, extracted with dichloromethane twice. Combined organic extracts were washed with water, 1 N HCl twice, water, brine and dried (MgSO4). Solvent was removed under vacuum, and the solid was washed with hexane to afford 4-bromo-2-fluoro-benzamide 2BL (5.56 g).
Reaction SMILES: COC1C(=O)C(=O)C=1[NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1.N>CS(C)=O.CO>[NH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[NH:24][CH2:25][C:26]2[C:27]3[C:28](=[CH:11][CH:10]=[CH:15][CH:14]=3)[N:29]=[CH:30][CH:31]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1c(Nc2cccc(NC(=O)c3sccc3NCc3ccncc3)c2)c(=O)c1=O
Agent: N
Solvent: CO
Solvent: CS(C)=O
Product: Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Reaction time: 6 h

Procedure:
To a solution of N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]phenyl}-3-[(pyridin-4-ylmethyl)amino]thiophene-2-carboxamide (EXAMPLE 1) (50 mg, 0.01 mmol) in DMSO (150 μL) was added a 2M solution of ammonia in methanol (650 μL). The reaction was left for 6 h at rt. The reaction was then purified by reverse phase HPLC using a gradient of 5→65% MeCN/H2O over 15 min at 15 mL/min. Removal of the solvent provided EXAMPLE 3 as a white solid. MS (ES): m/z 469.9 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=5.06 (d, J=6.0 Hz, 2H), 6.82 (d, J=5.6 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.39 (d, J=4.4 Hz, 1H), 7.61 (d, J=5.2 Hz, 1H), 7.64-7.68 (m, 2H), 7.78 (t, J=7.2 Hz, 1H), 8.02-8.06 (m, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.83 (d, J=4.4 Hz, 1H), 9.48 (s, 1H), 9.78 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li+:13].[Cl-:14].[CH:15]12[O:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2>C(O)(C)C>[OH:21][CH:16]1[CH:17]([N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH:17]3[CH:16]([OH:21])[CH2:15][CH2:20][CH2:19][CH2:18]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:18][CH2:19][CH2:20][CH2:15]1.[Li+:13].[Cl-:14]
Reactant: C1CNCCNCCNCCN1
Reactant: C1CCC2OC2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)O
Product: OC1CCCCC1N1CCNCCN(C2CCCCC2O)CCNCC1
Temperature: 0 °C

Procedure:
10 g (58.08 mmol) of 1,4,7,10-tetraazacyclododecane, 4.85 g (116.16 mmol) of LiCl and 56.5 g (580.0 mmol) of cyclohexene oxide (7-oxabicyclo[4.1.0]heptane) are suspended in 20 ml of isopropanol and refluxed for 20 hours. Then, the reaction mixture is mixed with 30 ml of isopropanol and slowly cooled to 0° C. The crystals that are obtained are suctioned off, washed with 30 ml of methyl-tert-butyl ether and dried in a vacuum. 19.5 g (82% of theory) of 1,7-bis(6-hydroxycyclohexyl)-1,4,7,10-tetraazacyclododecane LiCl complex is obtained as white crystals. Melting point 170-178° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1CC(=O)c1cccc(I)c1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C(=O)c1cccc(I)c1)c1ccccc1C

Procedure:
A solution of 1-(3-iodophenyl)-2-(2-methylphenyl)ethanone (3.21 g) in dry tetrahydrofuran (30 mL) is treated with methyl acrylate (0.9 mL) and potassium tertiary butoxide (0.107 g). The reaction mixture is heated at reflux for 18 hours, evaporated and the residue partitioned between ethyl acetate (60 mL) and water (30 mL). The organic phase is dried over magnesium sulphate, evaporated and the residual solid washed with pentane to give methyl (RS)-5-(3-iodophenyl)-4-(2-methylphenyl)-5-oxopentanoate as a fawn coloured solid (3.39 g), m.p. 106-108° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH:27]=O)[CH:21]=4)[C:16]3=[O:29])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>N1C=CC=CC=1.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH:27]=[N:31][OH:32])[CH:21]=4)[C:16]3=[O:29])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=CCOc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cc1)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1c2ccc(OCC=NO)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of the above aldehyde (~23 mmol) in pyridine (20 ml) and EtOH (20 ml) is added hydroxylamine hydrochloride (3.2 g, 46 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc (300 ml) and 2N HCl (300 ml). The EtOAc portion is washed with saturated NaHCO3 solution (300 ml), saturated NaCl solution (300 ml), dried over MgSO4, and concentrated in vacuo. The resulting material is purified by chromatography (silica gel 1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes and 2:3 EtOAc/hexanes) yielding α-[2-(4'-fluoro-4-biphenylylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-acetaldehyde oxime.
Reaction SMILES: [N:1]#[N:2].C(O[C:8]([N:10](C)[C@@H:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=O)(C)(C)C.C(OCC)(=O)C.[ClH:35]>>[N:1]#[N:2].[ClH:35].[CH3:8][NH:10][C@@H:11]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:17])[CH2:12][CH2:13][S:14][CH3:15]
Reactant: CSCC[C@H](C(=O)NCCCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CN[C@H](CCSC)C(=O)NCCCc1ccccc1

Procedure:
A solution of N2 -(tert-butyloxycarbonyl)-N2 -methyl-N-(3-phenylpropyl)-D-methioninamide (3.3 g.) in hydrogen chloride-ethyl acetate (3.4 N, 18 ml.) was stirred for one half hour at room temperature, then stripped of volatiles, affording N2 -methyl-N-(3-phenylpropyl)-D-methioninamide hydrochloride as a crystalline solid (2.5 g., m.r. 107°-110° C.).