Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:5]([C:12]([O:14][CH2:15]C)=[O:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:7]=1)[CH3:2].O.[OH-].[Li+].[C:57]([O:63]CCl)(=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59]>>[CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:5]([C:12]([O:14][CH2:15][O:63][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:13])=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[N:7]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 100.2 %

Procedure:
Following a procedure similar to that described in Example 78(a), but using 2.25 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 68(a)] and using 203 mg of lithium hydroxide monohydrate for hydrolysis and 0.90 g of pivaloyloxymethylchloride for esterification, 2.53 g of the title compound wet obtained as a glass (purified by column chromatography through silica gel using a 1:1 by volume mixture o f ethyl acetate and hexane as the eluent).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH3:5][C:6]([CH3:11])([CH3:10])[C:7](Cl)=[O:8]>N1C=CC=CC=1>[CH3:5][C:6]([CH3:11])([CH3:10])[C:7]([O:4][CH2:1][CH:2]=[CH2:3])=[O:8]
Reactant: C=CCO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: C=CCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 432.5 %

Procedure:
A stirred solution of 11.6 grams (0.20 mole) of 2-propen-1ol in 100 ml of pyridine was heated to reflux. To this was added dropwise 24.1 grams (0.02 mole) of trimethylacetyl chloride. The exothermic reaction caused the reaction mixture temperature to become excessive. The heat source was removed, and the reaction mixture was cooled in an ice bath. The addition of the acid chloride was continued to completion. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for one hour. After this time the reaction mixture was cooled to ambient temperature where it stood for 60 hours. The reaction mixture was shaken with 700 ml of water, and the organic layer was separated. The aqueous layer was washed with two 15o ml portions of diethyl ether. The washes and the organic layer were combined and washed with two 75 ml portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. Low boiling volatile materials were removed from the oil by distillation under reduced pressure (b.p. 87°-100° C./21 mm), yielding 12.3 grams of 2-propenyl trimethylacetate as a residue. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:35])[CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]([OH:35])[CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2nc(-c3ccc(S(C)(=O)=O)cc3)ncc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(-c3ccc(S(C)(=O)=O)cc3)ncc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (50 mg) is added to an ice-cooled solution of 4-{2-[5-chloro-2-(4-methanesulfonyl-phenyl)-pyrimidin-4-yl]acetyl}-piperidine-1-carboxylic acid tert-butyl ester (280 mg) in a mixture of tetrahydrofuran (10 mL) and water (2 mL). The ice bath is removed after 5 min and the reaction mixture is stirred for 0.5 h at room temperature. 2 N Citric acid is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 40:60→0:100) to give the title compound. LC (method 7): tR=1.48 min; Mass spectrum (ESI−): m/z=494 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:16][CH:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=3)=[O:18])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:16][CH:15]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[CH:21][CH:20]=3)=[O:18])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CC(C(=O)c3ccc(F)cc3)C2)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CCN2CC(C(=O)c3ccc(-n4ccnc4)cc3)C2)cc1OC

Procedure:
In a manner similar to Example 26, react [1-[2-(3,4-dimethoxyphenyl)ethyl]azetidin-3-yl](4-fluorophenyl)-methanone with 1H-imidazole to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:36][N:37]1[C:41]([CH3:42])=[CH:40][C:39]([CH2:43][N:44]2[C:52]3[CH:51]=[CH:50][CH:49]=[C:48]([NH2:53])[C:47]=3[C:46]([CH2:54][CH3:55])=[N:45]2)=[N:38]1>CN1C(=O)CCC1.[OH-].[Na+].CCOC(C)=O>[CH3:36][N:37]1[C:41]([CH3:42])=[CH:40][C:39]([CH2:43][N:44]2[C:52]3[C:47](=[C:48]([NH:53][C:20]([C:17]4[N:14]5[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:12][C:13]5=[N:19][CH:18]=4)=[O:22])[CH:49]=[CH:50][CH:51]=3)[C:46]([CH2:54][CH3:55])=[N:45]2)=[N:38]1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(N)c12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Temperature: 87 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (89.1 mg, 0.278 mmol) in NMP (6 mL) at 0° C. was added 2,4,6-trichlorobenzoyl chloride (43.5 μL, 0.278 mmol). The reaction mixture was stirred for 30 minutes. 1-((1,5-Dimethyl-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-amine (50 mg, 0.186 mmol) was added and the mixture was heated at 87° C. for 3 hours. The reaction mixture was cooled to ambient temperature, and diluted with 10% NaOH aqueous solution (5 mL) and EtOAc (20 mL). The organic phase was washed with water and brine and then concentrated under reduced pressure. The residue was triturated with Et2O to give final product (71 mg). MS (ES+APCI) m/z=556 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@H](C)[C@H](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)C(O)=O)[C:2]1C=CC=CC=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52]COC2CCCCO2)=[CH:47][CH:46]=1)[C:42]([OH:44])=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].C[C@@H]1CO1>>[C:33]([O:37][C:38]([NH:40][C@H:41]([C:45]1[CH:46]=[CH:47][C:48]([O:51][CH2:52][C@H:1]([OH:8])[CH3:2])=[CH:49][CH:50]=1)[C:42]([OH:44])=[O:43])=[O:39])([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C[C@@H]1CO1
Product: C[C@@H](O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 3 except that (i) 2-chloro-4-iodo-aniline was used in place of 4-bromo-2-chloro-aniline in step 1, and (ii) (R)-tert-butoxycarbonylamino-[4-((R)-2-hydroxy-propoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2. (R)-tert-Butoxycarbonylamino-[4-((R)-2-hydroxy-propoxy)-phenyl]-acetic acid was prepared as described in example 48 except that (R)-2-methyl-oxirane was used in place of 2-(2bromo-ethoxy)-tetrahydropyran.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>>[N:28]1[NH:29][C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:3][CH2:2]3)[CH:17]=[CH:16]4)=[CH:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: CCC(=O)Cl
Reactant: c1cc(-c2ccc(Oc3ccc4nc(CN5CCNCC5)ccc4c3)cc2)[nH]n1
Product: CCC(=O)N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1

Procedure:
The title product (12) is prepared from intermediate F (40.0 mg, 0.087 mmol) and propionyl chloride (9.5 μL, 0.11 mmol) according to the procedure described for the synthesis of Example 10.
Reaction SMILES: C1(COC(=O)[NH:10][C@@H:11]([CH2:20][OH:21])[C:12](=[O:19])[NH:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)C=CC=CC=1>CO.[Pd]>[NH2:10][C@@H:11]([CH2:20][OH:21])[C:12]([NH:13][N:14]1[CH:15]=[CH:16][CH:17]=[CH:18]1)=[O:19]
Reactant: O=C(N[C@@H](CO)C(=O)Nn1cccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H](CO)C(=O)Nn1cccc1

Procedure:
(S)-Phenylmethyl-[1-(hydroxymethyl)-2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (4.90 g) was dissolved in 100 ml of methanol over 5% Pd/C (500 mg). The solution was hydrogenated at atmospheric pressure and room temperature until absorption of 80% of the theoretical amount of hydrogen. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography (silica gel, ethyl acetate/methanol 4:1) In afford the desired product as a powder. Recrystallization from ethyl acetate/methanol/hexane gave the product as needles (1.37 g), m.p, 135°-137° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][N+:7]=2[O-])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:11]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-n2ccnc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccnc(-n2ccnc2)c1
Temperature: 100 °C

Procedure:
A 0.12 g portion of 2-(1-imidazolyl)-4-nitropyridine N-oxide was suspended in 14 ml of 70% ethanol aqueous solution, 0.32 g of iron powder and 20 mg of ammonium chloride were added in that order to the suspension and then the mixture was heated at 100° C. for about 20 minutes. Then, the insoluble matter was immediately removed by filtration, and the resulting filtrate was evaporated under reduced pressure to obtain 0.1 g of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=1)(=O)=O.[Cl:24][C:25]1[C:26](B(O)O)=[CH:27][C:28]([F:31])=[N:29][CH:30]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:24][C:25]1[C:26]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:8]=2)=[CH:27][C:28]([F:31])=[N:29][CH:30]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: O=S(=O)(Oc1ccc(F)c(NCC2CCOCC2)n1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1cc(-c2ccc(F)c(NCC3CCOCC3)n2)c(Cl)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-fluoro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-yl trifluoromethanesulfonate (712 mg, 1.987 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (697 mg, 3.97 mmol), PdCl2(dppf).CH2Cl2 adduct (162 mg, 0.199 mmol) in DME (8 mL) and 2 M aqueous Na2CO3 solution (2.6 mL, 1.987 mmol) in a sealed tube was heated at 95° C. for 3 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (˜100 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 (2×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=0/100 to 25/75 over 20 min] providing 5′-chloro-2′,5-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine as a white solid. Yield: 570 mg. LCMS (m/z): 340.1 [M+H]+; Retention time=0.99 min.
Reaction SMILES: NCC1C=C(C2C=CC=C3C=2CCCN3C(=O)CCCOC2C=CC=C(C)C=2C)C=CC=1.CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=C(C=CC=3)CNC(=O)OC(C)(C)C)C=CC=2)CCC1)=O.[CH3:72][C:73]1[C:119]([CH3:120])=[CH:118][CH:117]=[CH:116][C:74]=1[O:75][CH2:76][CH2:77][CH2:78][C:79]([N:81]1[C:90]2[C:85](=[C:86]([C:91]3[CH:92]=[N:93][N:94]([CH2:96][C:97]4[CH:98]=[C:99]([CH:113]=[CH:114][CH:115]=4)[C:100]([NH:102][CH2:103][CH2:104][NH:105]C(=O)OC(C)(C)C)=[O:101])[CH:95]=3)[CH:87]=[CH:88][CH:89]=2)[CH2:84][CH2:83][CH2:82]1)=[O:80]>>[NH2:105][CH2:104][CH2:103][NH:102][C:100](=[O:101])[C:99]1[CH:113]=[CH:114][CH:115]=[C:97]([CH2:96][N:94]2[CH:95]=[C:91]([C:86]3[CH:87]=[CH:88][CH:89]=[C:90]4[C:85]=3[CH2:84][CH2:83][CH2:82][N:81]4[C:79](=[O:80])[CH2:78][CH2:77][CH2:76][O:75][C:74]3[CH:116]=[CH:117][CH:118]=[C:119]([CH3:120])[C:73]=3[CH3:72])[CH:92]=[N:93]2)[CH:98]=1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(C(=O)NCCNC(=O)OC(C)(C)C)c5)c4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CN)c4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(C(=O)NCCN)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-(3-(aminomethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that tert-butyl 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzylcarbamate was replaced with tert-butyl 2-(3-((4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)methyl)benzamido)ethylcarbamate. LCMS, [M+H]+=566.3. 1H NMR (400 MHz, MeOD) δ 7.89-7.73 (m, 2H), 7.65 (s, 1H), 7.56-7.40 (m, 3H), 7.32-7.19 (m, 2H), 7.17 (br. s, 1H), 6.96 (t, J=7.9 Hz, 1H), 6.71-6.59 (m, 2H), 5.43 (s, 2H), 3.86 (br. s, 2H), 3.74 (t, J=6.8 Hz, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.90 (t, J=6.3 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 2.48 (br. s, 2H), 2.12 (dt, J=12.4, 6.3 Hz, 2H), 2.03 (s, 3H), 1.85-1.75 (m, 2H), 1.74 (s, 3H).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]([CH2:18][C:19](OCC)=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1cc(-c2ccccc2)c2c(O)cc(O)cc2o1

Procedure:
A solution of phloroglucinol (2.00 g) and ethyl benzoylacetate (3.05 g) in ethanol (30 ml) was treated with dry HCl as described in example 1a. The product was recrystallized from ethanol-water (1:1). Yield 3.0 g (75%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[C:22]([S:33]([OH:36])(=O)=[O:34])=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=1.[NH3:37]>>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[C:22]([S:33]([NH2:37])(=[O:36])=[O:34])=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)c(OC)c3S(=O)(=O)O)n2C)n(CCC)c1=O
Reactant: N
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)c(OC)c3S(N)(=O)=O)n2C)n(CCC)c1=O
Yield: 11 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.80 g (3.45 mmol) of Compound 11 obtained in Example 10 and 1.0 ml of conc. aqueous ammonia. The resulting crude crystals were recrystallized from acetonitrile to give 200 mg (yield 11%) of Compound 12 as yellow needles.
Reaction SMILES: C(OC([N:8]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:9]([C:11]1[N:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[N:14]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[N:17]=2)[CH:15]=1)=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:44]1[CH2:43][CH2:42][CH:41]([NH:8][C:9]([C:11]2[N:12]=[C:13]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:40])[F:39])[CH:32]=3)[N:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])[N:17]=3)[CH:15]=2)=[O:10])[CH2:46][CH2:45]1
Reactant: C[C@H](Nc1nccc(-n2cc(C(=O)N(C(=O)OC(C)(C)C)C3CCNCC3)nc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1nccc(-n2cc(C(=O)NC3CCNCC3)nc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
(S)-1-[2-(1-Phenyl-ethylamino)-pyrimidin-4-yl]-2-(3-trifluoromethyl-phenyl)-1H-imidazole-4-carboxylic acid-N-t-butoxycarbonylpiperidin-4-ylamide (600 mg) was dissolved in 10 mL CH2Cl12 and cooled to 0° C. before adding 3 mL TFA. The reaction was allowed to warm to room temperature and stirred for 1 h. Concentration and prep HPLC on a Delta-Pak™ 40 mm×200 mm C8 column from 100/0 H2O/CH3CN to 5/95 H2O/CH3CN over 30 min yielded 280 mg of the title compound after lyophilization as a granular solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[O:19])[CH2:14][CH2:13]2)[CH:4]=[C:3]1[C:26](O)=[O:27].[N:29]1([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>>[N:29]1([C:35]2[CH:36]=[C:37]([NH:41][C:26]([C:3]3[N:2]([CH3:1])[C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][C:9]=4[CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[CH3:25])=[O:19])[CH2:16][CH2:17]3)=[O:27])[CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: CN1CCCC1C(=O)N1CCN(Cc2cccc3cc(C(=O)O)n(C)c23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC[C@H]1C(=O)N1CCN(Cc2cccc3cc(C(=O)Nc4cccc(N5CCOCC5)c4)n(C)c23)CC1

Procedure:
1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid and 3-morpholin-4-yl-phenylamine are used as reactants. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU) is used instead of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[CH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.[Cl-].[Na+]>O.C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]2([O:10][N:9]=[C:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:18])([CH3:14])([CH3:13])[CH3:15]
Reactant: ON=C(Cl)Cc1ccccc1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Cc1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound W (3.33 g, 20 mmol), dissolved in abs. DCM (15 ml), was added dropwise at 0° C. within 10 min to a solution of compound B (2.81 g, 14.3 mmol in abs. DCM (22 ml)). A solution of triethylamine (11.2 ml, 80 mmol) in abs. DCM (10 ml) was added to this mixture at 0° C. within 10 min. As the reaction was highly exothermic, cooling was carried out with a mixture of ice and sodium chloride. The reaction mixture was stirred for 16 h at RT. For working up the mixture, DCM (15 ml) and water (45 ml) were added and the mixture was stirred for 15 min. After separation of the phases, the aqueous phase was extracted with DCM (2×45 ml). The phases were separated. The organic phase was washed successively with 10% citric acid solution (2×30 ml) and sat. NaCl solution (30 ml). The organic phase was dried and concentrated (5.3 g, brown oil). The residue was separated by chromatography [silica gel 60 (180 g); cyclohexane/EtOAc 7:1 (1,200 ml); 5:1 (900 ml)]. The desired product X was obtained in a yield of 681 mg (11%).
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a solution of Boc-D-Phe-Pro-OBn (145 g, 320 mmol) in p-dioxane (660 mL) was added a solution of lithium hydroxide monohydrate (54 g, 1,280 mmol) in water (330 mL) with vigorous stirring. After 4 hours, the solution was concentrated in vacuo to about one-fourth the original volume and diluted with water (350 mL) and 0.1N sodium hydroxide (100 mL). The aqueous phase was washed three times with diethyl ether (250 mL) and then acidified to pH 3 with solid citric acid which caused a precipitate to form. The solid was filtered, washed twice with water, and then dried under high vacuum, to yield 91 g (78%) of a white solid.
Reaction SMILES: Br[CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)CCC>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:2]2[N:19]3[C:15]([S:16][CH:17]=[CH:18]3)=[N:14][C:3]=2[CH3:4])=[CH:7][CH:8]=1)#[N:11]
Reactant: Nc1nccs1
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1nc2sccn2c1-c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 4-(1-bromo-2-oxopropyl)benzonitrile (1 g, 4 mmol) in n-butanol (3 ml) was added in a single portion to a hot (110° C.), stirred solution of 2-aminothiazole in n-butanol (3 ml). After refluxing for 2 hours, triethylamine (0.5 ml, 4 mmol) was added and heating was resumed for a further 2 hours. All volatiles were evaporated and the residue was chromatographed on silica gel, eluting with ethyl acetate:hexane:diethylamine (5:14:1) to afford an off-white solid (0.34 g, 35%), m.p. 88°-91° C.