Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cncs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
In THF (5.0 ml)/methanol (10 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g). To the solution was added 1N sodium hydroxide solution (5.0 ml), and the mixture was stirred at room temperature for 16 hours. pH was adjusted to approximate 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane ethyl acetate (8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (385 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([CH:41]=1)[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)=[C:37]([C:38]([N:13]2[CH2:12][CH2:11][C@@H:10]3[C@@H:15]([N:8]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=4)[CH2:9]3)[CH2:14]2)=[O:39])[CH:41]=1
Reactant: Cc1cnc(N2C[C@@H]3CCNC[C@@H]32)cn1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)cn1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(5-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 29) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CD3OD): 8.06-7.72 (m, 4H), 7.61-7.47 (m, 1H), 7.41-6.53 (m, 2H), 4.70-3.75 (m, 5H), 3.58-2.88 (m, 3H), 2.43-1.93 (m, 5H).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]3[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].Br[CH2:32][CH:33]1[O:37][CH2:36][CH2:35][O:34]1.[I-].[Na+]>>[O:34]1[CH2:35][CH2:36][O:37][CH:33]1[CH2:32][N:21]1[CH2:22][CH2:23][C:17]2[C:16]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[N:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=3)=[N:19][C:18]=2[CH:20]1[CH3:24]
Reactant: BrCC1OCCO1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3C)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(CC2OCCO2)C3C)cc1

Procedure:
The compound sj was prepared following the general procedure in Example 296, substituting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt for 1-ethyl-3-(4-(8-methyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt and substituting 1-bromo-2-methoxyethane for 2-(bromomethyl)-1,3-dioxolane. For this reaction, a catalytic amount Sodium iodide was also added: LC-MS m/z=483 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([NH:25]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:10]([O:12][NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Product: CC(C)C[C@@H](C(=O)ONC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate is prepared from (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoic acid and N-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compound exists as rotomers and is reported as such. (1.8 g, 58%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49-8.06 (1H, m), 4.75-5.10 (1H, m), 2.86 (3 H, d, 7.8 Hz), 1.66-1.88 (2H, m), 1.54-1.64 (1H, m), 1.50 (9H, s), 1.47 (9H, d, 3.7 Hz), 0.96 (6H, dd, 10.7, 6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:54][C:55]1[CH:66]=[CH:65][C:58]2[NH:59][C:60]([C@@H:62]([NH2:64])[CH3:63])=[N:61][C:57]=2[CH:56]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:54][C:55]1[CH:66]=[CH:65][C:58]2[NH:59][C:60]([C@@H:62]([NH:64][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:10]([N:4]4[C:5]5[CH2:9][CH2:8][CH2:7][C:6]=5[C:2]([CH3:1])=[N:3]4)=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=3)[CH3:63])=[N:61][C:57]=2[CH:56]=1
Reactant: Cc1nn(-c2ccc(C(=O)O)cc2C(F)(F)F)c2c1CCC2
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nn(-c2ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc2C(F)(F)F)c2c1CCC2
Yield: 47 %

Procedure:
Prepared analogously to Example 1g from 4-(3-methyl-5,6-dihydro-4H-cyclopentapyrazol-1-yl)-3-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 47%; Rf value: 0.30 (silica gel: dichloromethane/ethanol=9:1); C24H21ClF3N5O (487.911); mass spectrum: (M+H)+=488/490 (chlorine isotope) and (M−H)−=487/489 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)CCl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N+:18]3[O-:39])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: [O-][n+]1c(-c2ccccc2)ccc2ccc(-c3nc(C4CCC4)n4ccnc(Cl)c34)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (ice-H2O) solution of 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline (197 mg, 0.48 mmol) in ClCH2CH2Cl (20 mL) was added mCPBA (97 mg, max 0.43 mmol, max. 77% Aldrich) in one portion. The solution was stirred at the temperature for 30 min and then allowed to warm to rt by removing the cooling bath and stirred at rt (2 h). The reaction mixture was again cooled (ice-H2O) and treated with another portion of mCPBA (107 mg, max 0.48 mmol), stirred for 30 min at the temperature and then overnight at rt (15 h). After that time the crude mixture was filtered through hydromatrix (25 mL) pretreated with 2 M aq NaOH (10 mL). The hydromatrix column was washed with DCM (˜100 mL) and the filtrate was concentrated under reduced pressure. The resultant yellow residue was purified by flash chromatography on silica gel (70 g cartridge, 0→0.75→4% MeOH in DCM) to yield 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline 1-oxide as a yellow gum. A cooled (−10° C.) i-PrOH (15 mL) solution of 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline 1-oxide (50 mg) in a Parr bomb was saturated with NH3(g) for 3 min. The vessel was sealed and heated at 100-110° C. (bath temperature) for 2 d. The reaction mixture was then cooled to rt, concentrated under reduced pressure and purified by flash chromatography on silica gel (0-4% MeOH+2% ˜6 M NH3 in MeOH. A trituration with hexanes (3×) provided the title material as a bright yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.16 (dd, J=8.2 Hz, 1.8 Hz, 1H), 8.04-7.96 (m, 3H), 7.79 (d, J=8.8 Hz, 1H), 7.57-7.43 (m, 4H), 7.16 (d, J=5.2 Hz, 1H), 7.13 (d, J=4.8 Hz, 1H), 5.30 (s, 2H), 3.85 (quintet, J=8.2 Hz, 1H), 2.69-2.60 (m, 2H), 2.55-2.50 (m, 2H), 2.30-2.15 (m, 1H), 2.15-2.00 (m, 1H); MS (ES+): m/z 408.13 (100) [MH+]; HPLC: tR=2.14 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:18](=[O:19])[C:17]2[NH:16][CH:15]=[N:14][C:13]=2[N:12]([CH3:20])[C:10]1=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:30])([O:31][CH2:32][CH3:33])[O:27][CH2:28][CH3:29])[CH:15]=[N:14][C:13]=2[N:12]([CH3:20])[C:10]1=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: Cn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]cnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(Cc1ccccc1)c(=O)n2C)OCC
Temperature: 70 °C
Reaction time: 6 h

Procedure:
20 g (0.078 mol) of 1-benzyl-3-methylxanthine hydrochloride, 21.4 g (0.094 mol) of diethyl 4-chlorobutanephosphonate and 26 g (0.2 mol) of potassium carbonate were suspended in 400 ml of dimethylformamide and stirred at 70° C. for 6 hours. The solution was filtered hot and the dimethylformamide was evaporated under reduced pressure. The oily residue which remained was taken up in dichloromethane and washed several times with water. After evaporating the solvent, it was possible to reuse the pale yellow, oily residue without purification.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[C:8]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:7]1[CH3:26])C.[OH-].[Na+].Cl>C(O)C>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:7]=2[CH3:26])(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O
Reaction time: 1 h

Procedure:
The product of step (c) was dissolved in ethanol (10 ml) and 10% NaOH (aq) (10 ml) was added and stirred for 1 h. The reaction mixture was then acidified with HCl (aq), and extracted with EtOAc. Purification by solid phase extraction using NH2 sorbent (2 g), eluting with acetonitrile followed by 10% acetic acid/acetonitrile, gave the title compound (0.301 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(F)c1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-fluorobenzylamine (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 49 mg of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][NH:31][CH3:32]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([N:31]([CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])[CH3:32])=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Reactant: CNCCN(C)C
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)CCN(C)C)cc2[nH]1
Yield: 13 %

Procedure:
The title compound was prepared as a white solid (10 mg, 13% yield for 3 steps) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg, crude, STEP 4 in Example 4) and N,N,N′-trimethyl-1,2-ethanediamine (45 mg, 0.44 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH:13]1[C:14]2[N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)[C:16]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a suspension of sodium hydride (60% mineral oil, 0.13 g, 3.24 mmol) in dimethyl formamide (3 ml) was added phenoxazine (0.5 g, 2.7 mmol) in dimethyl formamide (5 mL). The reaction mixture was stirred at 25° C. for 0.5 h and a solution of 4-(2-bromoethoxy)benzaldehyde (0.74 g, 3.24 mmol) in dimethyl formamide (3 mL) was added. The reaction mixture was stirred at 25° C. for 6 h. Water (25 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 ml), brine solution (50 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (3:7) as eluent to afford the title compound (0.52 g, 57%) as a syrupy liquid.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:19])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2=[N:7]1)[C:3]#[N:4].[O:21]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:19][C:12]1[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:36][CH:35]=1)([C:3]#[N:4])[CH3:20])[N:7]=2
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(C(F)(F)F)c2n1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(C(F)(F)F)c2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 32) and 4-phenoxybenzoyl chloride (0.10 mL), the title compound was isolated as a white solid (95 mg, 58%). Rf=0.75 (1:1 EA/heptane). MS (ES): M/Z [M+H]=500. NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 2.47 (s, 3H), 5.47 (d, J=13.3 Hz, 1H), 5.57 (d, J=13.3 Hz, 1H), 7.04-7.12 (m, 4H), 7.22 (t, J=7.4 Hz, 1H), 7.97 (s, 1H), 8.57 (s, 1H) and 8.69 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −61.41 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:16][CH2:15][CH2:14][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: COc1cc(OC)c(C=O)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cc(OC)c(C2OCCO2)cc1Br
Reaction time: 6 h
Yield: 91.5 %

Procedure:
Ex-46A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.92 g, 20.1 mmol) was dissolved in benzene (41 mL). Ethylene glycol (3 mL, 54 mmol) and p-toluenesulfonic acid (25 mg, 0.13 mmol) were added and the solution was refluxed with a Dean-Stark trap attached. After 6 h, the reaction was cooled and washed with water (1×20 mL), saturated, aqueous NaHCO3 (1×20 mL), and water (1×20 mL). The organic phase was dried over sodium sulfate, filtered, concentrated, and dried to provide 5.32 g of 2-(5-bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane as a faint yellow oil which solidified upon standing (92% yield). 1H-NMR (CDCl3) δ 7.67 (s, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 4.11–4.13 (m, 2H), 3.98–4.03 (m, 2H), 3.91 (s, 3H), 3.87 (s, 3H). HRMS (ES+) Calcd. for C11H13BrO4: 289.0075. Found: 289.0077.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>C(#N)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([O:11][CH2:12][C@@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(=O)N2)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N[C@H](COc2ccc(Br)cc2)CO1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A solution of Example 1C (4.154 kg), potassium carbonate (2.522 kg), and 4-bromophenol (3.183 kg) in acetonitrile (30.3 kg) was stirred at 70° C. for 23.5 hours, cooled to 55° C., treated with 2% (w/w) K2CO3 (41.52 kg) over 20 minutes, cooled to room temperature, and separated into an aqueous fraction and an organic fraction. The organic fraction was concentrated to approximately one third of its original volume, treated with the aqueous fraction to provide a precipitate, concentrated to remove the remainder of the acetonitrile, treated with the 2% (w/w) K2CO3 solution (41.52 kg), stirred at room temperature for 18 hours, and filtered. The filter cake was rinsed with 2% K2CO3 (16.62 L) air-dried, slurried in ethyl acetate (9.44 kg), and heated at 55° C. This solution was treated with hexanes (23.615 kg) and cooled to room temperature to provide a solid. The solid was filtered, rinsed with a solution of ethyl acetate (2.24 kg) and hexanes (7.3 kg), air dried, and vacuum dried (100 mnu/Hg) at 50° C. with a nitrogen bleed to provide 3.307 kg (79.6%, >99.5% ee) of the desired compound. 1H NMR (300 MHz, DMSO-d6) δ7.91 (br s, 1H), 7.47 (dd, J=17 Hz, 2H), 6.93 (dd, J=17 Hz, 2H), 4.44 (m, 1H), 4.15 (m, 2H), 3.95 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)=[C:13](C(OCC)=O)[C:12]2=[O:32])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:32])[CH:13]=[C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc3ncccc3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: O=C1C=C(Nc2ccc3ncccc3c2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 12.5 %

Procedure:
A solution of the compound (0.075 g, 0.18 mmol) of Example 44 in N,N-dimethylformamide (4.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0080 g, y. 13%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)[CH:27]=[CH:26][C:23]=1[C:24]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]3[C@@H:15]4[CH2:16][C@@H:12]([CH:13]=[CH:14]4)[C@@H:11]3[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N2CCN(C)CC2)ccc1C=O
Product: COc1cc(N2CCN(C)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)ccnc2[nH]1
Yield: 20.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 2-methoxy-4-(4-methyl-piperazin-1-yl)-benzaldehyde (49.7 mg, 0.212 mmol) were reacted to produce 19 mg (21%) of the title compound. mp: 185-195° C., 1H NMR (300 MHz, DMSO-d6): 11.87 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.16 (s, 1H), 6.73 (m, 1H), 6.68 (s, 1H), 6.60 (s, 1H), 6.37 (s, 1H), 6.32 (s, 2H), 3.95 (s, 4H), 2.86 (s, 1H), 2.75 (s, 1H), 2.24 (s, 4H), 1.42 (s, 1H), 1.24 (s, 1H). MS: 474 (M+H), HPLC: 1.59 min (G method).
Reaction SMILES: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CO.[CH:16]1([CH2:22][C@H:23]2[C@H:27]([C@H:28]([CH:32]3[CH2:34][CH2:33]3)[N:29]=[N+:30]=[N-:31])[O:26]C(C)(C)[N:24]2C(OC(C)(C)C)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[NH2:24][C@@H:23]([CH2:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C@@H:27]([OH:26])[C@@H:28]([N:29]=[N+:30]=[N-:31])[CH:32]1[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](N=[N+]=[N-])C2CC2)OC1(C)C
Agent: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CO
Product: [N-]=[N+]=N[C@@H](C1CC1)[C@H](O)[C@@H](N)CC1CCCCC1

Procedure:
In a manner analogous to the procedure described above for the preparation of (2RS,3R,4S)-4-amino-5-cyclohexyl-1,2,3-pentanetriol, by reacting tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclopropylazidomethyl]-2,2-dimethyl-3-oxazolidinecarboxylate there is obtained (1S,2R,3S)-3-amino-1-azido-4-cyclohexyl-1-cyclopropyl-2-butanol as an oil, MS: 253 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:15]([OH:17])=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[NH:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:15]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
7.67 g (40.0 mmol) of EDCl was added to 50 ml of THF solution of 3.50 g (20.0 mmol) of Boc-Gly-OH (manufactured by Tokyo Chemical Industry Co., Ltd), and 1.82 ml (20.0 mmol) of aniline, followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed with brine (two times for each), and the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1 to 1/1 (volume ratio)), thereby obtaining 4.85 g of the product with a yield of 96.9%.