Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:27]([CH:24]5[CH2:26][CH2:25]5)=[O:28])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)C1CC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CC4)nc3cc21

Procedure:
Cyclopropanecarboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and cyclopropanecarbonyl chloride (152 mg, 1.45 mmol). The title compound was obtained as white powder (23 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11]Br)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.C([O-])(=[O:17])C.[K+].CO.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][OH:17])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Fc1cc(Br)c2occ(CBr)c2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: OCc1coc2c(Br)cc(F)c(F)c12
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
The compound (1.47 g, 4.51 mmol) obtained in Step 1 was dissolved in acetonitrile (50 mL), and potassium acetate (660 mg, 6.76 mmol) was added thereto, and stirred at 60° C. for 3 hours. After cooling, the solvent was distilled away, and to the resulting residue, methanol (20 mL) and potassium carbonate (1.56 g, 11.28 mmol) were added, and stirred at room temperature for 2 hours. The solvent was distilled away. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:4][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.4 %

Procedure:
To a solution of 7.18 g (71 mmol) of 4-hydroxypiperidine in 100 ml dimethylformamide are added first 19.6 g (142 mmol) of powdered potassium carbonate and then 19.8 9 (71 mmol) of tritylchloride. The mixture is stirred for 22 hours at ambient temperature, diluted with ethyl acetate to twice the volume, washed with water and saturated saline solution, dried with magnesium sulphate and concentrated by evaporation. The residue is recrystallised from ethyl acetate/petroleum ether (1:4, v:v). 17.65 g (72.4% of theory) of 4-hydroxy-N-tritylpiperidine are obtained as colourless crystals, melting point 157-158° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[Cl-].[F:25][C:26]1[CH:27]=[C:28]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:29][NH2+:30][CH2:31][C:32]([NH:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][C@@:39]1([C:47](=[O:48])[NH:46][C:45](=[O:49])[N:44]1[CH3:50])[CH2:38]2)=[O:33]>C(Cl)Cl.CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:29][N:30]([CH2:31][C:32]([NH:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][C@@:39]1([C:47](=[O:48])[NH:46][C:45](=[O:49])[N:44]1[CH3:50])[CH2:38]2)=[O:33])[C:8]([C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:10]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)C[NH2+]Cc3cc(F)cc(F)c3)cc1C2
Reactant: CC1(C(=O)O)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN(Cc3cc(F)cc(F)c3)C(=O)C3(C)CCCCC3)cc1C2
Temperature: 0 °C

Procedure:
To a solution of 1-methylcyclohexanecarboxylic acid (32.0 mg, 0.222 mmol) in DCM (1.5 mL) was added one drop of DMF (cat.), followed by oxalyl chloride (37.0 mg, 0.228 mmol), while at ambient temperature and under a constant stream of nitrogen. Upon cessation of gas evolution, the reaction mixture was cooled to 0° C. prior to the introduction of triethylamine (34.0 mg, 0.333 mmol) as a solution in DCM (2.0 mL), and then N-(3,5-difluorobenzyl)-2-{[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]amino}-2-oxoethanaminium chloride (50.0 mg, 0.111 mmol, Intermediate 1). After 1 hour the reaction mixture was applied directly to a silica gel column for purification, eluting with DCM:MeOH—99:1 to 95:5. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=561 (M+23(Na+)). HRMS: m/z=539.2477; calculated m/z=539.2464 for C29H33N4O4F2.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@H:4]([O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1)[C@@H:5]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[O:22])[CH:18]=[C:17]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[CH3:37][N:32]([S:33]([CH3:36])(=[O:35])=[O:34])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[O:22])[CH:18]=1)[C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:4]([O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1)[C:3]([OH:46])=[O:2])=[O:38]
Reactant: COC(=O)[C@H](OC1CCCCO1)[C@H](Cc1ccccc1)NC(=O)c1cc(C(=O)N[C@H](C)c2ccccc2)cc(N(C)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](OC2CCCCO2)C(=O)O)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
The (2R,3S)-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)benzoyl]amino}-4-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)butanoic acid methylester obtained in Reference Example 26 1.79 g (2.75 mmol) was dissolved in methanol 6 mL and thereto was added 5N aqueous sodium hydroxide solution 1.10 mL under ice-cooling and the mixture was stirred at room temperature for 6 hours. After distillating methanol off, the mixture was washed with ether. The aqueous layer was adjusted with diluted hydrochloric acid to pH 3 under ice-cooling and extracted with chloroform. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on magnesium sulfate, filtered and concentrated to give 1.74 g (2.73 mmol) of the title compound (yield: 99%).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9](N(OC)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:24]1>>[CH2:1]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:9](=[O:10])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 26.7 g of tert-butyl (1R)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate in 534 cm3 of tetrahydrofuran dried over 4 Å sieves is cooled, under an inert atmosphere, to a temperature in the region of 0° C. 87 cm3 of a 3 M solution of methylmagnesium bromide in diethyl ether are then added over 45 minutes and the resulting mixture is then stirred for 1 hour at 0° C. and for 18 hours at room temperature. The reaction medium is re-cooled to a temperature in the region of 0° C., 55 cm3 of 1N hydrochloric acid are then added dropwise and the mixture is stirred for 30 minutes at this temperature. After filtration through Celite, 200 cm3 of water are added to the filtrate, which is then extracted with twice 200 cm3 of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 21.2 g of tert-butyl (1R)-1-benzyl-2-oxopropylcarbamate are obtained in the form of yellow crystals melting at 59° C. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.34 (s: 9H); 2.13 (s: 3H); 2.71 (dd, J=14 and 10 Hz: 1H); 3.01 (dd, J=14 and 5 Hz: 1H); 4.13 (mt: 1H); from 7.10 to 7.35 (mt: 6H).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:19]([O-])=O)[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[OH:23]S(O)(=O)=O.O=S(=O)=O.B(O)(O)O.[S]>>[OH:23][C:14]1[C:15]2[C:16](=[O:18])[C:17]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[NH2:1])[C:9](=[O:22])[C:10]=2[C:11]([NH2:19])=[CH:12][CH:13]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: OB(O)O
Agent: [S]
Product: Nc1cccc2c1C(=O)c1c(O)ccc(N)c1C2=O

Procedure:
100 parts of 1,5-dinitroanthraquinone are reduced as indicated in Example 3 with 35% strength oleum in the presence of boric acid by means of sulphur. The batch is then discharged onto 4,000 parts of ice and the product is filtered off with suction. After washing until neutral, 98 parts of 1-hydroxy-4-amino-8-nitroanthraquinone are obtained in the form of a 38% strength presscake, which can be reduced, for example to give 1-hydroxy-4,8-diaminoanthraquinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:26]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Reactant: COC1=CCCCCCCCC1
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCCCCC1
Yield: 65.7 %

Procedure:
The compound 8 (375 mg, 1 mmol) was converted to the enol ether with 1-methoxy-1-cyclodecene (505 mg, 3 mmol) in the same manner as the example 10 to give the compound 12 (336 mg, 66%) as oil. Rf 0.55 (Al2O3 60, Type E, 10:1 toluene - EtOAc).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C([NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1)(=[O:36])=[O:35])(C)(C)C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:40]3[CH:41]=[CH:42][C:37]([S:34]([NH2:33])(=[O:36])=[O:35])=[N:38][CH:39]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 31b was subjected to Suzuki coupling reaction conditions with compound 32b using the methods described in Example 1, Step G, and the resulting product was subjected to TFA deprotection using the methods described in Example 1, Step E, to obtain title compound 86. 1H-NMR (400 MHz, CD3OD) δ (ppm): 8.85 (s, 1H), 8.08-8.15 (m, 2H), 8.03 (d, J=9.0 Hz, 1H), 7.84 (s, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.59-7.65 (m, 1H), 7.43 (s, 1H), 7.35-7.41 (m, 2H), 6.95 (d, J=9.0 Hz, 1H), 5.64 (s, 2H), 4.32 (br. s., 4H), 3.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H23N7O4S: 518.1 (M+H). Found 518.2.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]2[CH2:15][CH:14]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:13][C:12]2=[O:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH2:31].[OH-].[Li+]>O.C1COCC1>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:15][CH:14]([OH:31])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]([OH:13])=[O:24])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: O
Reactant: O=C1OC(CSc2ccccc2)CC1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC(O)CSc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 3-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-2-oxo-5-[(phenylthio)methyl]-tetrahydrofuran 16c (0.18 g, 0.41 mmol) in water (5 mL) and THF (5 mL) is added slowly lithium hydroxide monohydrate (172 mg, 4.1 mmol). The reaction mixture is stirred for 3 hr, then concentrated to dryness. The resulting mixture is diluted with water, and then the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9](S(C3C=CC=CC=3)=O)[C:8]2=[O:21])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:21])=[CH:22][CH:23]=1
Reactant: O=C1C(S(=O)c2ccccc2)CCCN1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1C=CCCN1Cc1ccc(F)cc1

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one (0.37 g, 1.11 mmol) in toluene (15 mL) was added solid Na2CO3 (2 g, 18.8 mmol). The reaction mixture was refluxed for about 6 hours. The resultant solution was filtered and concentrated under vacuum and the residue chromatographed on silica eluting with a gradient of 040% EtOAc/Hexanes to give the product as colorless glass.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]=[C:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>C(Cl)Cl>[OH:20][CH2:19][CH2:21][NH:22][C:13]([NH:12][CH2:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: O=C=NCc1ccccc1OCc1ccccc1
Reactant: NCCO
Solvent: ClCCl
Product: O=C(NCCO)NCc1ccccc1OCc1ccccc1

Procedure:
A solution of 73.6 g of crude 2-benzyloxybenzyl isocyanate in 120 ml of methylene chloride is added dropwise in the course of 50 minutes to a solution of 36.8 ml of ethanolamine in 370 ml of methylene chloride. The reaction is slightly exothermic. After 2 hours the reaction solution is washed three times with 200 ml of water each time and dried using sodium sulphate. Methylene chloride is distilled off and the residue is recrystallised from isopropanol. The resulting product melts at 92°-94°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[N:28]1([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:31]3[CH2:32][CH2:33][N:28]([C:34]4[S:35][CH:36]=[CH:37][N:38]=4)[CH2:29][CH2:30]3)=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: c1csc(N2CCNCC2)n1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCN(c4nccs4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (30 mg, 0.083 mmol) in N,N-dimethylformamide (1 mL) were added 2-(piperazin-1-yl)thiazole (40 mg, 0.24 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mol) and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:7]=1)=[O:5])C.Cl>C(O)(=O)C>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[F:18])[N:8]([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Yield: 85 %

Procedure:
6,7-Difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (14.5 g, 42 mmol) was mixed with acetic acid (300 ml), treated with 1N hydrochloric acid (100 ml) and heated to 100° for 4 hours. The reaction mixture was cooled and filtered, and the precipitate washed with water and ethyl ether to provide the title product as a solid, m.p. 252°-256° (11.5 g, 36.0 mmol, 85% yield).
Reaction SMILES: [NH2:1][CH:2]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4](OCC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[NH2:1][CH:2]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH2:12]1)[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)CC(N)C1(c2ccc(Cl)cc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NC(CCO)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 16 h

Procedure:
A solution of ethyl 3-amino-3-[1-(4-chlorophenyl)cyclobutyl]propanoate (5 g prepared as described in Example 137) in ether (25 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (3 g) in ether (50 ml). The mixture was heated under reflux for 3 hours, allowed to stand for 16 hours with no heating and then heated under reflux for a further 6 hours. Water (3 ml) was added dropwise with stirring to the cooled reaction mixture followed by 15% aqueous sodium hydroxide solution (3 ml) and water (9 ml). The reaction mixture was filtered and the residue washed with ether. The filtrate and the washings were combined, washed with water then brine and dried. Evaporation of the solvent gave a residue which was recrystallised from petroleum ether (b.p. 40°-60° C.) to give 3-amino-3-[1-(4-chlorophenyl)cyclobutyl]propan-1-ol (m.p. 98°-99° C.).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=[O:13])[C:3]1=[O:17].[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=[O:17]
Reactant: CCOC(=O)c1nc2ccccc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(=O)c(C(=O)O)nc2ccccc21
Temperature: 25 °C
Yield: 98.7 %

Procedure:
3.0 g (12.9 mmol) of ethyl 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in ethanol (100 mL), and 4.1 g (25.6 mmol) of a 25% aqueous solution of sodium hydroxide was added dropwise thereto at room temperature. The mixture was stirred for a day at room temperature, and then the reaction mixture was concentrated under reduced pressure. Water was added to the reaction mixture, and the solution was acidified using 10% hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the inorganic matter was separated by filtration. Then, the solvent was distilled off under reduced pressure, to obtain 2.6 g (yield: 99%) of 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid as a milky yellow powder.
Reaction SMILES: [N+:1]([C:4]([N+:23]([O-:25])=[O:24])([N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][C:7]([NH:9][NH:10][C:11](=[O:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCCl.C(Cl)Cl>[N+:1]([C:4]([N+:23]([O-:25])=[O:24])([N+:20]([O-:22])=[O:21])[CH2:5][CH2:6][C:7]1[O:19][C:11]([C:12]([F:17])([F:18])[C:13]([F:15])([F:16])[F:14])=[N:10][N:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[N+]([O-])C(CCc1nnc(C(F)(F)C(F)(F)F)o1)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A solution containing 0.6 g (0.0016 mole) of N-(4,4,4-trinitrobutyryl)-N'-(perfluoropropionyl)hydrazine and 0.8 g (0.0038 mole) of phosphorus pentachloride in 7 mL of 1,2-dichloroethane was held at reflux temperature for 4 hours before the volatiles were removed to give an oil residue. The residue was dissolved in CH2Cl2, washed with water, and chromatographed on Silica gel 40 (CH2Cl2 as eluent) to give the product, 2-(3,3,3-trinitropropyl)-5-(perfluoroethyl)-1,3,4-oxadiazole, 0.4 g (70%), mp 36°-38° C. 1H NMR (acetone-d6): 3.80 (m, 2H), 4.20 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[O:4][CH:5]=1
Reactant: C1COCCN1
Reactant: O=c1cc(CBr)occ1O
Solvent: CC#N
Product: O=c1cc(CN2CCOCC2)occ1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
2-(Bromomethyl)-5-hydroxy-4H-pyran-4-one 21 (5.0 g, 24.4 mmol), morpholine (4.3 mL, 48.8 mmol) and acetonitrile (120 mL) were charged in a 250 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture was stirred for 3 h at 80° C. Acetonitrile was evaporated and the residu was extracted with EtOAc (400 mL). The organic layer was washed with water (20 mL), brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. Diethyl ether (25 mL) was added and the product was precipitated and filtered to give after drying 5-hydroxy-2-(morpholinomethyl)-4H-pyran-4-one 22 (4.8 g, 72% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]>O=[Mn]=O.C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(CO)c1C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccnc(C=O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A CH2Cl2 solution (10 mL) of (3,4-dimethyl-pyridin-2-yl)-methanol (271 mg, 1.98 mmol) (Katz, R. B. et al. Synth. Commun. 1989, 19, 317-25) was treated with MnO2 (2.10 g, 21.8 mmol), and the resultant black suspension was stirred at room temperature overnight. The black suspension was filtered through a celite pad and the filtrate was concentrated in vacuo to afford 3,4-Dimethyl-pyridine-2-carbaldehyde (215 mg, 80%), without further purification, as a red oil. 1H NMR (CDCl3) δ 2.37 (s, 3H), 2.60 (s, 3H), 7.22-7.29 (m, 1H), 8.52 (d, 1H, J=4.3 Hz), 10.20 (s, 1H).