Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C2C3(CCN(C(OC(C)(C)C)=O)CC3)CN(C3C4[C@H](C)C[C@@H](OC(=O)C5C=CC([N+]([O-])=O)=CC=5)C=4N=CN=3)C2=CC=1.[N+](C1C=CC(C([O:54][C@H:55]2[C:59]3[N:60]=[CH:61][N:62]=[C:63]([N:64]4[C:84]5[C:79](=[C:80]([CH2:85][NH:86][C:87](=[O:89])[CH3:88])[CH:81]=[CH:82][CH:83]=5)[C:66]5([CH2:71][CH2:70][N:69]([CH2:72][C:73]6[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=6)[CH2:68][CH2:67]5)[CH2:65]4)[C:58]=3[C@H:57]([CH3:90])[CH2:56]2)=O)=CC=1)([O-])=O>>[CH2:72]([N:69]1[CH2:68][CH2:67][C:66]2([C:79]3[C:84](=[CH:83][CH:82]=[CH:81][C:80]=3[CH2:85][NH:86][C:87](=[O:89])[CH3:88])[N:64]([C:63]3[C:58]4[C@H:57]([CH3:90])[CH2:56][C@@H:55]([OH:54])[C:59]=4[N:60]=[CH:61][N:62]=3)[CH2:65]2)[CH2:71][CH2:70]1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1
Reactant: CC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Product: CC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2O

Procedure:
N-((1′-benzyl-1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)acetamide was prepared by the procedures described in Example 3, Step 12, substituting (tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate with (5R,7R)-4-(4-(acetamidomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate. LCMS (APCI+) m/z 498 [M+H]+; Rt=2.16 min.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Cl[CH2:13][C:14]#[C:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.O>[O:17]([CH2:16][C:15]#[C:14][CH2:13][S:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC#CCOc1ccccc1
Reactant: N#Cc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(SCC#CCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of potassium hydroxide (7.5 g) in a mixture of ethanol (220 ml) and water (55 ml) was added at ambient temperature under nitrogen to a stirred solution of 4-mercaptobenzonitrile (18.0 g; prepared according to the method of S. Krishnamurthy and D. Aimino, J. Org. Chem., 1989, 54, 4458) in a mixture of ethanol (195 ml) and water (12 ml), then the mixture was stirred at ambient temperature for 4.5 hours. A solution of 1-chloro-4-phenoxybut-2-yne (24.1 g; prepared in a similar manner to that described in Example 5) in a mixture of ethanol (195 ml) and water (12 ml) was added dropwise over 1.5 hours, then the mixture was stirred at ambient temperature for 17 hours. The mixture was concentrated in vacuo to remove the ethanol, then the product was diluted with water (150 ml) and extracted into ethyl acetate (2×250 ml). The combined extracts were washed with water (100 ml) and saturated brine (100 ml), dried (MgSO4), and the solvent removed in vacuo to leave 4-(4-phenoxybut-2-ynylthio)benzonitrile as an off-white solid (37.7 g).
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([N:30]=[C:31]=[O:32])[CH2:28][CH3:29]>O1CCCC1>[CH2:27]([NH:30][C:31](=[O:32])[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH:6]=[CH:7]2)[CH2:28][CH3:29]
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: CCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCNC(=O)Oc1ccc2c(ccn2N(CCC)c2ccncc2)c1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.1 g) in 50 ml of tetrahydrofuran was added potassium carbonate (milled, 1.3 g). Then propyl isocyanate (0.67 g) was added and the reaction mixture was stirred for 2 hours. The mixture was filtered and the filtrate was concentrated to yield an oil (2.8 g), which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil which solidified on standing (2.5 g), m.p. 120°-122° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:28]=[N:27]C=2C=1.O.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH:27][NH2:28])=[O:8]
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: ClCCl
Product: NNC(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 160.2 %

Procedure:
To a round-bottom flask was added a solution of (S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (40 mL). EDC.HCl (7.50 g, 39.1 mmol, 1.50 equiv), HOBT (5.20 g, 38.5 mmol, 1.50 equiv), and hydrazine hydrate (2 mL, 2.00 equiv, 99%) were added to the reaction. The resulting solution was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo to furnish 5.38 g (80%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O:6][C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][C:20](=O)[CH2:21][C:22](OCC)=[O:23])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:8].[Li+].[OH-]>C(O)(C)(C)C.[OH-].[Na+].CCOC(C)=O>[O:23]=[C:22]1[NH:4][C:2](=[S:3])[NH:1][C:20]([CH2:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:9]([C:7]([OH:8])=[O:6])=[CH:10][CH:11]=[CH:12]3)=[CH:21]1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)Cc1ccc2c(C(=O)OC)cccc2c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2cc(Cc3cc(=O)[nH]c(=S)[nH]3)ccc12
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
3.46 g (45.4 mMol) thiourea are added to a solution of 29.7 mMol 6-(3-ethoxycarbonyl-2-oxo-propyl)-naphthalene-1-carboxylic acid methyl ester in 25 ml tert-butanol. Then 13.3 g (119 mMol) potassium tert-butyrate are added (exothermic). After 50 min, the mixture is heated for 4.5 h in an oil bath of 100° C. Cooling to rt gives an almost solid mixture, which is redissolved by addition of 59 ml of a 1 M aq. solution of LiOH and stirring during 40 min. This solution is diluted with 500 ml of a 0.33 M solution of NaOH and EtOAc. The organic phase is separated off, washed with 300 ml of a 0.33 M solution of NaOH and discarded. The aq. phases are acidified by addition of 2 N HCl (pH=3), the precipitated product filtered off, washed with 0.001 N HCl and dried in vacuo at 80° C. The crude material is stirred in a boiling mixture of 0.6 l CH3CN, 60 ml EtOAc, 120 ml MeOH and 120 ml THF. Filtration of the hot suspension then leads to the title compound: m.p.: 334-337° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[OH:32][CH2:28][CH2:29][C:30]#[C:31][C:13]1[CH:12]=[C:11]2[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:10]2)=[CH:15][CH:14]=1
Reactant: C#CCCO
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: OCCC#Cc1ccc2c(=NO)cc(-c3cc4ccccc4cn3)oc2c1

Procedure:
7-(4-Hydroxy-but-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 10% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-butyn-1-ol. The title compound was isolated as a yellow solid and as a 70/30 mixture of Z/E oxime isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][OH:27])[CH:34]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (2.5 g, 5.98 mmol), (3-(hydroxymethyl)phenyl)boronic acid (1 g, 6.57 mmol) and Pd(PPh3)4 (0.69 g, 0.598 mmol) in 1,4-dioxane (30 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 (2.3 g, 21.69 mmol) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (2.1 g, 80.7%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:5]=2[N:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[CH:22]=[N:23][C:24](F)=[CH:25][C:26]=3[CH3:27])=[O:20])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:5]=2[N:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([N:31]4[CH2:32][CH2:33][O:29][C:30]4=[O:34])=[N:23][CH:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 32.3 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(2,4-dicyclopropylphenyl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (500 mg) described in Preparation Example 142 and oxazolidin-2-one (459 mg), the title compound (190 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:33][N:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C6CN(C)C6)c5)cc4c3)n2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (194 mg, 0.4898 mmol) in dichloromethane (9 mL) was added formaldehyde (37% in water, 1.959 mmol, 147 uL). The solution was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (260 mg, 1.22 mmol) was added. After 1 hour the solution was diluted with dichloromethane (6 mL) and washed with sodium bicarbonate (6 mL). The aqueous layer was extracted further with dichloromethane (6 mL). The combined dichloromethane layers were washed with brine (12 mL) and dried over Na2SO4. The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH:NH4OH, 95:4.995:0.005-80:19.98:0.02) to return the title compound (69 mg, 35% yield). Analytical data presented in Table 2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15]C(OCC3C=CC=CC=3)=O)[C:9]=2[CH:8]=[N:7]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N
Yield: 100.3 %

Procedure:
A solution of ((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (357 mg, 1.0 mmol) in ethanol was hydrogenolyzed over 10% palladium on carbon (40 mg) under atmospheric pressure at room temperature for 3 hours. The reaction mixture was then filtered through a pad of Celite® (diatomite filter). The filtrate was collected, and concentrated in vacuo to afford ((R)-4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (224 mg, 99%) as a light yellow oil. MS calcd. for C11H17N3O2 223, obsd. (ESI+) [(M+H)+] 224.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>ClCCl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][O:5][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)CCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCC[Si](C)(C)C
Yield: 44.7 %

Procedure:
2-Trimethylsilylethanol (Aldrich) (30 g, 0.25 mole) was placed in a round bottom flask equipped with a condenser, addition funnel, magnetic stirrer and a nitrogen inlet. 200 ml dichloromethane, pyridine (20.80 g, 0.26 mole) and 100 mg of phenothiazine were added to the flask. While stirring, methacryloyl chloride (27.18 g, 0.26 mole) in 100 ml dichloromethane was added dropwise at room temperature. A mildly exothermic reaction occurred. The mixture was stirred overnight at room temperature. Afterwards, the mixture was washed with 1×100 ml deionized water and 2×100 ml brine and dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo. Fractional distillation under reduced pressure gave 20.82 grams of the desired product at 35-38° C. at 0.5 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH:18]=1)[O:7][CH:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1.C([O-])=O.[NH4+]>CO.[Pd]>[O:12]1[C:11]2([CH2:16][CH2:17][CH:8]([O:7][C:6]3[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[NH2:19])[CH2:9][CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CCC2(CC1)OCCO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(F)cc1OC1CCC2(CC1)OCCO2
Reaction time: 0.5 h

Procedure:
0.446 g Pd/C (5%) were added to a mixture of 4.46 g (8-(5-fluoro-2-nitro-phenoxy)-1,4-dioxa-spiro[4.5]decane and 4.03 g ammonium formate in 50 ml anhydrous methanol at rt. The reaction was initiated by gentle warming. The reaction was allowed to cool and stirred for a further 0.5 hours. The suspension was filtered through celite and washed with methanol. The combined organics were concentrated in vacuo and the residue triturated from diethylether. The solids were filtered and the filtrate collected and concentrated in vacuo to yield a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:26]=O)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:28]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CO.CC(O)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][NH:36][CH2:35][CH2:34][CH2:33][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCCCN1CCCC1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2CNCCCN2CCCC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2′-formyl-biphenyl-4-carboxylic acid quinolin-7-ylamide, Example 28, (50 mg, 0.14 mmol), 3-pyrrolidin-1-yl-propylamine (54 mg, 0.42 mmol, Aldrich) in DMF (1 mL) and MeOH (1 mL) was added glacial AcOH (1 drop), and the mixture was stirred at 50° C. for 30 min. Sodium triacetoxyborohydride (136 mg, 0.64 mmol) was added in small portions and the reaction mixture was stirred at 50° C. for 30 min. The reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was dissolved in EtOAc (60 mL) and washed with 0.5 N NaOH (10 mL). The EtOAc layer was separated, washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (gradient, 5 to 10% (2 M NH3 in MeOH) in CH2Cl2) to provide the title compound as light-yellow oil. MS (ESI, pos. ion.) m/z: 465 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[Br:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: COc1cc(Br)cc(C=O)c1O
Product: COc1cc(Br)cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(5-Bromo-2-hydroxy-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromo-2-hydroxy-3-methoxybenzaldehyde. Mass spectrum (ES) MH+=395.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:26](=O)[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+]>CO.C(#N)C>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([CH:26]([NH2:35])[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethanone (275 mg, 0.656 mmol) and ammonium acetate (506 mg, 6.56 mmol) in methanol (3.7 mL) and acetonitrile (3.7 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (82.5 mg, 1.31 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C22H35ClN3OSi (M+H)+: m/z=421.2; Found: 421.1.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmehyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=[C:6]([O:5][C:4]3[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: COC[C@H](C)Oc1cc(Oc2cc(F)cc(F)c2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3cc(F)cc(F)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(3,5-difluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][NH2:16])=[N:3][CH:4]=1
Reactant: CC(C)(C)COc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(NN)nc1

Procedure:
6.2 g (30.8 mmol) 2-chloro-5-(2,2-dimethylpropoxy)pyridine together with 60 ml (1.2 mol) hydrazine hydrate are divided into four portions of equal size and 10 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. (200 watt) for in each case 12 h. Thereafter, the four mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed in each case once with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed in vacuo.