Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2Cl>CN(C=O)C>[CH2:3]([O:10][C:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([Br:11])[CH:13]=2)[N:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2nccc(OCc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 60% NaH in mineral oil (1.75 equiv.) in DMF (0.5 M) was added benzyl alcohol (2.5 equiv.) dropwise. After stirring for 30 minutes, 6-bromo-4-chloroquinoline (1.0 equiv.) was added and the solution was heated in a microwave at 100° C. for 30 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed further with H2O (3×) and NaCl(sat.), dried over MgSO4, concentrated and triturated with hexanes to yield 4-(benzyloxy)-6-bromoquinoline (73%). LC/MS=314.0/315.9 (M+H), LC=2.89 min.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:8]=2[C:9](O)=[O:10])=[C:4]([NH:20][C:21]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[O:22])[CH:3]=1.[CH3:29][NH2:30].C1COCC1>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:8]=2[C:9]([NH:30][CH3:29])=[O:10])=[C:4]([NH:20][C:21]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[O:22])[CH:3]=1
Reactant: COc1cccc(Oc2ccc(F)cc2NC(=O)Nc2nccs2)c1C(=O)O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(OC)cccc1Oc1ccc(F)cc1NC(=O)Nc1nccs1
Yield: 72 %

Procedure:
2-[4-Fluoro-2-(3-thiazol-2-yl-ureido)-phenoxy]-6-methoxy-N-methyl-benzamide (150 mg, 72%) was prepared from 2-[4-fluoro-2-(3-thiazol-2-yl-ureido)-phenoxy]-6-methoxy-benzoic acid (201 mg, 0.5 mmol) and 1N solution of methyl amine in THF (0.5 mL, 0.5 mmol) following the general procedure K.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O>CO.[Pd]>[C:9]([C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:13]2)=[CH:12][CH:11]=1)#[N:10]
Reactant: CN(C)C=Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc2cc[nH]c2c1
Yield: 72.5 %

Procedure:
4-(2-Dimethylamino-vinyl)-3-nitro-benzonitrile (28.5 g, 131 mmol) was dissolved in MeOH (850 mL) and hydrogenated over 10% Pd/C (6.0 g) at 60 psi for 1.5 h at room temperature. The reaction was filtered over celite and evaporated in vacuo. The residue was partitioned between 5% aqueous HCl solution and Et2O (2×200 mL) and the combined organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6-cyano-1H-indole (13.5 g, 72%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) 11.7 (1H, br s), 7.89 (1H, s), 7.72 (1H, d, J=8.2 Hz), 7.65 (1H, m), 7.32 (1H, m), 6.59 (1H, m); MS m/e 141 (M−H)−. Anal calcd. for C9H6N2.0.10 H2O: C, 75.09; H, 4.34; N, 19.46. Found: C, 74.92; H, 4.29; N, 19.34.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[CH3:17][S:18][C:19]1[S:23][C:22]([SH:24])=[N:21][N:20]=1.N12CCCN=C1CCCC=C2>CN(C)C=O.CCOCC>[CH3:9][C:8]([C:6]1[CH:7]=[C:2]([S:24][C:22]2[S:23][C:19]([S:18][CH3:17])=[N:20][N:21]=2)[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: CSc1nnc(S)s1
Agent: C1=CN2CCCN=C2CCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1nnc(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Yield: 18.1 %

Procedure:
A solution of 4-bromo-2,6-di-t-butylphenol (3.0 g, 10.5 mmol), 5-methylthio-1,3,4-thiadiazole-2-thiol (2.0 g, 12.2 mmol), and 1,8-diazabicyclo-[5.4.0]undecen-7-ene (1.8 mL, 12.0 mmol) in dimethylformamide (120 mL) is stirred at 55° to 70° C. for 48 hours. The reaction mixture is cooled and diluted with ether then washed four times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a solid residue which is crystallized from ethyl acetate/hexane yielding 2.4 g (63%) of analytically pure light brown platelets; mp 144.0°-145.0° C. The mother liquor is chromatographed on silica gel eluting with 1:9 then 2:8 ethyl acetate:hexane to yield an additional 0.7 g (18%) of 2,6-bis(1,1-dimethylethyl)-4-[[5-(methylthio)-1,3,4-thiadiazol-2-yl]thio]phenol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CN1CCOCC1.[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CN
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Glycine methyl ester hydrochloride was suspended in tetrahydrofuran, the suspension was cooled to -5° C. to -10° C., and then half of the N-methylmorpholine was added. Cinnamoyl chloride was added immediately, followed by the other half of the N-methylmorpholine. The reaction mixture was stirred for 30 minutes at low temperature, then it was allowed to warm to room temperature and stirring was continued for 2 to 3 hours. After being diluted with ethyl acetate (about 750 ml) the solution was washed with water (three times), an aqueous solution of 0.5 N hydrochloric acid (three times) and finally with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with petroleum ether is order to induce crystallization. The product was left to stand for about 14 hours at 4° C., then it was filtered off and dried in a vacuum. It was used in the next step without further purification. 31 g of product were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[CH:50]1([CH2:56][CH2:57][O:58][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:31]=[CH:30][C:29]([N:32]6[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:34](=[O:47])[CH2:33]6)=[CH:28][CH:27]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:48][CH:49]=3)=[CH:4][CH:3]=2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)cc2)S1(=O)=O
Reactant: OCCC1CCCCC1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCCC5CCCCC5)nn4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (38 mg, 0.05 mmol) was treated as described in general procedure L using 2-cyclohexyl ethanol (35 μL, 0.25 mmol) to give 5-{-4-[2-{-4-[6-(2-cyclohexyl-ethoxy)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][CH:2]=1.OC1C2C(=CC=CC=2)C(O)=CC=1C>>[C:4]1(=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:12])[CH:2]=[CH:3]1
Reactant: Oc1ccc(O)c2ccccc12
Agent: Cc1cc(O)c2ccccc2c1O
Product: O=C1C=CC(=O)c2ccccc21
Yield: 93 %

Procedure:
Using the same procedure, napthalene- 1,4-diol and 1,4-dihydroxy-2-methyl-naphthalene were oxidized to obtain a 93% yield of 1,4-naphthoquinone and a 97% yield of 2-methyl-1,4-naphthoquinone, respectively.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1.[OH:34]O>C(O)(=O)C.O>[CH3:1][S:2]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)=[O:34]
Reactant: OO
Reactant: CSc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(C)c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2S(C)=O)c1

Procedure:
The compound of example 4 (100 mg, 0.216 mmol) was dissolved in acetic acid (7.5 ml), hydrogen peroxide (74 mg of a 30% solution in water, 0.65 mmol) was added, and the mixture was reacted at room temperature for 9 h. The mixture was partitioned between EA and a 1% aqueous sodium sulfite solution, the aqueous phase extracted with EA, and the organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred with diethyl ether, filtered, and dried in vacuo to give 79 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][CH:9]=[O:10])[S:6][CH:7]=1.[SH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1)=[O:10]
Reactant: O=CNc1nc(CCl)cs1
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CNc1nc(CSc2ccncc2)cs1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
A mixture of 4-chloromethy-2-formylaminothiazole (1.86 g), 4-mercaptopyridine (1.23 g) and potassium carbonate (1.8 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-pyridylthiomethyl)thiazole (1.7 g, yield: 68.0%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:2]1.C1(=C/C2C=CC=CN=2)/CCC2C/1=CC=CC=2.C([Li])CCC.CCCCCC.O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:59].[Cl-].[Cl-].[Cr+3:62]>O1CCCC1>[Cl-:59].[Cl-:59].[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[Cr+2:62]
Reactant: C1=C(Cc2ccccn2)c2ccccc2C1
Reactant: [Cr+3]
Agent: C(=C1\CCc2ccccc21)\c1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Cr+2]C1=Cc2ccccc2C1Cc1ccccn1
Temperature: -100 °C
Reaction time: 0.75 h

Procedure:
A solution of 52.7 g of the above mixture of 2-(1H-inden-3-ylmethyl)pyridine and 2-[(E)-2,3-dihydro-1H-inden-1-ylidenemethyl]pyridine in a molar ratio of 10:9 in 550 ml of tetrahydrofuran was cooled to −100° C. 80.5 ml of a 15% strength n-butyllithium solution in hexane (0.1288 mol) were then slowly added dropwise. After the addition was complete, the reaction mixture was stirred at −100° C. for a further 45 minutes. The mixture was subsequently allowed to warm to room temperature. After stirring for a further 2 hours, the solution was cooled to −60° C. and 49 g (0.1288 mol) of chromium trichloride tris(tetrahydrofuran) were added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred for a further 10 hours at room temperature. The reaction mixture was then refluxed for 20 minutes and subsequently cooled to room temperature. The solid which had precipitated was filtered off and washed with hot tetrahydrofuran. The solid was subsequently washed with diethyl ether and dried under reduced pressure. This gave 24.9 g of (1-(2-pyridylmethyl)indenyl)chromium dichloride (59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]([C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[OH:20])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 37.6 %

Procedure:
4-Fluorobromobenzene (19.26 g) in tetrahydrofuran (280 ml) was cooled to −78° C. and n-butyllithium (2.66 M n-hexane solution; 42 ml) was added thereto dropwise over 10 minutes or more while agitating. The reaction mixture was agitated for 1 hour while keeping the temperature. Then, 4-fluorobenzaldehyde (12.42 g) was added thereto dropwise over 10 minutes or more while agitating. The reaction mixture was agitated for 2 hours while keeping the temperature. Subsequently, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then brought to room temperature. The tetrahydrofuran was removed under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography to thereby obtain the subject compound (8.28 g).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:23]2[S:24][CH:25]=[CH:26][N:27]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>CO>[CH3:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[CH:12]2)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(-c1nccs1)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc2[nH]c(-c3nccs3)cc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
To absolution of the compound obtained in the step of Example 2 (4) (39 mg) in methanol (1 ml), a 1N aqueous potassium hydroxide solution (0.2 ml) was added at 15 to 30° C. and the mixture was stirred at 60° C. for 1 hour. To the reaction mixture was added 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off under reduced pressure to obtain the desired product (27 mg).
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]3)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CS(C)=O>[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28]([C:2]#[N:1])[CH2:27][CH2:26]3)=[N:17]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a stirred mixture of 1.5g of cyanogen bromide 2.0 g of potassium carbonate and 30 ml of dimethylsulfoxide was added, dropwise, a solution of 2.8 g of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole in 30 ml of dimethylsulfoxide. The reaction mixture was stirred at ambient temperature for 1.5 hours and then poured into water. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by flash chromatography on silica gel, utilizing ethyl acetate-hexane (1:1) as the eluent, followed by recrystallization from isopropyl alcohol-water to yield 2.3 g (59%) of 4-(1-phenyl-1H-indazol-3-yl)-1-piperazine carbonitrile, m.p. 118°-120°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:12])(=[O:4])=[O:3].ClC1C=C(S(C)(=O)=O)C=CC=1O[CH2:17][C:18]1[C:23](C)=[CH:22][C:21]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:20][N:19]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[CH:20][N:19]=2)=[CH:7][C:6]=1[CH3:12])(=[O:3])=[O:4]
Reactant: Cc1cc(O)ccc1S(C)(=O)=O
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)cnc1COc1ccc(S(C)(=O)=O)cc1Cl
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)ccc1S(C)(=O)=O
Yield: 35 %

Procedure:
The title compound was prepared from tert-butyl 4-[(2-hydroxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1(2)) (64 mg, 0.219 mmol) and 4-methanesulfonyl-3-methylphenol (41 mg, 0.219 mmol) following a procedure analogous to that in Example 1(3) and (4) as a pale yellow amorphous (35 mg, yield 35%).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C@@H:20]([OH:35])[CH2:21][C@@H:22]([C:31]([OH:34])([CH3:33])[CH3:32])[C:23]([NH:25][CH2:26][C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]([NH:53][C@H:54](C(O)=O)[CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=[CH:58][CH:57]=2)=[O:52])[CH2:46][CH2:45]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]([NH:53][C@H:54]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:36][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[C@@H:20]([OH:35])[CH2:21][C@@H:22]([C:31]([OH:34])([CH3:33])[CH3:32])[C:23]([NH:25][CH2:26][C@@H:27]([CH3:30])[CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=[CH:58][CH:57]=2)=[O:52])[CH2:46][CH2:45]1
Reactant: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)CN1CCOCC1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 150 mg (0.25 mmoles) of (2S, 4S, 5S)-5-{N-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino}-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-[2(S)-methylbutyl]hexanamide (prepared as described in Example 1) in 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and diethyl ether was added to the residue. The solvent was then again removed by distillation under reduced pressure. This operation was repeated in total three times, and then the final residue was dried under vacuum for 8 hours. The dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and then 100 mg (0.29 mmoles) of N-morpholinoacetyl-3-(1-naphthyl)-L-alanine were added to the resulting suspension, followed by 0.04 ml (0.26 mmoles) of 95% diethyl cyanophosphate and 0.11 ml (0.79 mmoles) of triethylamine, all whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel thin layer chromatography (using a 10:1 by volume mixture of methylene chloride and methanol as eluent), to give 150 mg (yield 73%) of the title compound as white crystals, melting at 141°-143° C.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:20]=[C:19]3[N:30]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[N:31]=[C:32]([CH3:33])[C:18]=23)=O)[C@@H:10]([CH3:40])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:20]=[C:19]3[N:30]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[N:31]=[C:32]([CH3:33])[C:18]=23)[C@@H:10]([CH3:40])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c12
Temperature: 0 °C
Yield: 85.6 %

Procedure:
600 mg of ((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-[6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone were dissolved in 10 ml of THF. Under Argon-atmosphere, 1.1 ml of lithium aluminium hydride (2.4M in THF) was added and the reaction was heated to reflux for 2 h. The reaction was then cooled to 0° C., and quenched by the addition of 5 ml EtOAc and 5 ml water. The mixture was filtered over celite by suction and washed with EtOAc. The solvents were removed in vacuo and 500 mg (86%) of the title compound were obtained and used without further purification.
Reaction SMILES: Br[C:2](=[CH:5]OC(C)C)[CH:3]=[O:4].[S:10]1[CH2:14][C:13](=[NH:15])[NH:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[N:15]1[C:2]([CH:3]=[O:4])=[CH:5][N:12]2[C:13]=1[CH2:14][S:10][CH2:11]2
Reactant: N=C1CSCN1
Reactant: CC(C)OC=C(Br)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1cn2c(n1)CSC2
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 36.9 %

Procedure:
The solution of 2-bromo-3-isopropoxypropenal (6.9 g) in dry acetonitrile (326 mL) was added to the solution of crude thiazolidin-4-ylideneamine (3.3 g) in dry acetonitrile (326 mL) at room temperature. The reaction mixture was stirred at room temperature for 19.5 h, added triethylamine (4.9 mL) and then refluxed for 2 h. The reaction mixture was cooled to room temperature and then evaporated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50% potassium carbonate aqueous solution (20 g). After filtration and separation, the aqueous layer was extracted with dichloromethane (50 mL×4). The organic layers were combined, dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with CHCl3-MeOH (100:3) to obtain crude 7H-Imidazo[1,2-c]thiazole-2-carbaldehyde as a brown solid. The crude product was re-crystallized twice from CHCl3-n-hexane (1st: 30:5, 2nd: 30:60) at 0° C. to give the required aldehyde as pale brown crystals (Yield: 1.84 g, 15%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2C(=O)C3=CC=CC=C3C2=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.C([O-])([O-])=O.[K+].[K+]>C(O)C.[Cl-].[Na+].O>[NH2:17][CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
1-Benzyloxycarbonyl-4-phthalimidylpiperidine (1.50 g, 4.27 mmol), prepared in Example 16B, was taken up in 20 mL of ethanol. To this solution was added hydrazine monohydrate (35 mL, 700 mmol) and this mixture was heated at 100° C. for 3 h. Brine solution (40 mL) and 10% aq. K2CO3 (60 mL) were added and the mixture was extracted with 5% MeOH/CHCl3 (3×). The combined extracts were washed with 2N aq. HCl, 2N aq. NaOH, brine solution, dried over Na2SO4 and concentrated to give 0.847 g, (85%) of 4-amino-1-benzyloxycarbonylpiperidine. [1H]-NMR(CDCl3) consistent with structure.