Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:22]=3)[C:14]3[N:15]([CH:17]=[CH:18][N:19]=3)[N:16]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:22]=3)[C:14]3[N:15]([CH:17]=[CH:18][N:19]=3)[N:16]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(C(=O)[O-])cccc1-c1cc(Nc2cccc(N3CCC[C@@H]3C)n2)c2nccn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)O)cccc1-c1cc(Nc2cccc(N3CCC[C@@H]3C)n2)c2nccn2n1
Temperature: 40 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a solution of (S)-2-methyl-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (72 mg, 0.16 mmol) in dioxane (5 mL) and water (4 mL) was added NaOH (64 mg, 1.6 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated in vacuo, water (10 mL) was added and the solution was washed with dichloromethane (10 mL×3). The aqueous layer was adjusted to pH=4 by the addition of concentrated HCl. The solid formed was collected by filtration and was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give the final product (S)-2-methyl-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (41 mg, 59%). 1H NMR (300 MHz, DMSO): δ 10.43 (s, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 7.90 (d, 1H, J=7.5 Hz), 7.62-7.42 (m, 3H), 6.68 (d, 1H, J=7.8 Hz), 6.10 (d, 1H, J=8.1 Hz), 4.04-4.00 (m, 2H), 3.40-3.35 (m, 1H), 3.18-3.15 (m, 1H), 2.47 (s, 3H), 1.96-1.88 (m, 2H), 1.55-1.51 (m, 1H), 0.86 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 429, tR=1.619 min, HPLC: 100% at 214 nm, 99.42% at 254 nm, tR=5.838 min.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][Mg]Br)[CH3:2].C(OCC)C.[C:16](=S)([O:27]C1C=CC=CN=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>C1COCC1>[CH2:1]([CH:3]([CH2:4][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: C=CCCCCCCCCC(=S)Oc1ccccn1
Reactant: CCCCC(CC)C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCCCCCCCC(=O)CC(CC)CCCC
Reaction time: 0.5 h

Procedure:
A Grignard solution of 2-ethylhexylmagnesium-bromide in diethylether (1.0 M, 1.96 mL, 1.96 mmol) was slowly added via syringe to a stirred mixture of pyridin-2-yl undec-10-enethioate (0.54 g, 1.96 mmol) in THF (50 mL) at 0° C. under N2 atmosphere. After vigorously stirring for another 30 minutes, the reaction was completed by adding (2.0 M, 50 mL). The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with a saturated bicarbonate solution and brine, dried over MgSO4 and evaporated under reduced pressure to give a yellow oil. The resulting oil was purified by vacuum distillation at 90-100° C. at 10−2 mbar. 1H-NMR (CDCl3): δ=5.85-5.67 (m, 1H), 5.00-4.83 (m, 2H), 2.37-2.22 (m, 4H), 1.99 (q, J=14.0 Hz, J=6.9 Hz, 2H), 1.89-1.76 (m, 1H), 1.61-1.44 (m; 4H), 1.39-1.09 (m, 16H), 0.90-0.74 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:24])=O>C1COCC1.CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound 29d (100 mg, 0.35 mmol) in THF (2 mL) was added oxalyl dichloride (46 μL, 0.53 mmol) dropwise at 0° C., followed by addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, and was then warmed up to room temperature overnight. The solvents were removed under reduced pressure, and the residue, compound 29e, was dried under reduced pressure for 2 h and then used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=O)(=[O:10])=[O:9])[CH:2]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[S:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:10])[CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Reactant: CCCCN
Product: CCCCNC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Reaction time: 48 h
Yield: 82 %

Procedure:
The title compound was prepared according to procedures described above, using methyl 2-[(pyridin-3-ylamino)sulfonyl]benzoate and n-butylamine. The title compound was further purified by dissolving 2.0 g in ethyl acetate (10 mL). Hexane was then added dropwise to the solution until it became cloudy. A few drops of ethyl acetate were then added to obtain a clear solution. The resulting solution was left at rt for approximately 48 h. The resulting solids were collected, washed with 20% ethyl acetate/hexane (3×150 mL), and dried under high vacuum overnight at rt to afford the title compound as a crystalline solid (1.64 g, 82%). 1H NMR (400 MHz, DMSO-D6) δ 9.90-10.00 (m, 1H) 8.73 (t, 1H) 8.28-8.37 (m, 2H) 7.71-7.76 (m, 1H) 7.61-7.70 (m, 2H) 7.49-7.57 (m, 2H) 7.35-7.44 (m, 1H) 3.25 (q, 2H) 1.51-1.54 (m, 2H) 1.29-1.40 (m, 2H) 0.90 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH2:12][CH2:13][CH2:14][N:15]=2)=[CH:6][CH:5]=1)([O-])=O.[ClH:16].C>C(O)C>[ClH:16].[ClH:16].[NH:15]1[CH2:14][CH2:13][CH2:12][N:11]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C2=NCCCN2)cc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(C2=NCCCN2)cc1

Procedure:
A solution of the product of Stage (i) (20.5 g) in ethanol (150 ml) containing 2N hydrochloric acid (150 ml) was stirred in the presence of 10% palladised charcoal (2.0 g) under an atmosphere of hydrogen, until uptake ceased. The suspension was filtered through a pad of `hyflo`, the pad was washed with 50% aqueous ethanol (200 ml) and the combined filtrates evaporated under reduced pressure. Crystallisation of the residue from methanol-isopropyl acetate [1:1] (300 ml) gave the title compound as a powder (23.7 g), m.p.>300°.
Reaction SMILES: [Li][CH2:2]CCC.[C:6]1([CH:12]2[CH2:15][C:14](=O)[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[CH2:2]=[C:14]1[CH2:15][CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13]1
Reactant: O=C1CC(c2ccccc2)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a 2-3° C. suspension of methyltriphenylphosphonium bromide (0.36 g, 1 mmol) in THF (2.5 ml) was added dropwise n-BuLi (0.69 ml, 1.1 mmol, 1.6 M in hexan). After 1 hour stirring at 0° C., a solution of 3-phenyl-cyclobutanone (0.146 g, 1 mmol) in THF (1.5 ml) was added dropwise. The reaction mixture was stirred 24 hours at room temperature and then diluted with hexane. The so obtained precipitate was filtered and the filtrate was concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (3-methylene-cyclobutyl)-benzene (57 mg, 40%) as a slightly yellow oil, MS: m/e=144.1 (M+).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([C:19]#[N:20])[C:9]([O:15][CH2:16][O:17][CH3:18])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]>C(O)C>[OH:4][CH2:3][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([C:19]#[N:20])[C:9]([O:15][CH2:16][O:17][CH3:18])=[CH:10][CH:11]=2)[N:6]=1
Reactant: COCOc1ccc2ccc(C=O)nc2c1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCOc1ccc2ccc(CO)nc2c1C#N
Reaction time: 0.33 h
Yield: 989.9 %

Procedure:
Referring to FIG. 20, NaBH4 (0.0151 g, 0.400 mmol) was added to a solution of 9b (0.0240 g, 0.099 mmol) in ethanol (5 mL). The mixture was stirred for 20 min. The solvent was evaporated and the resulting residue was dissolved in chloroform, then washed with water followed by brine, dried over Na2SO4, concentrated, and purified by column chromatography (45:55 EtOAc/hexane) to yield 10b (0.0240 g, 0.98 mmol, 99%) as a white solid: 1H NMR (CDCl3) δ 8.14 (1H, d, J=8.0 Hz), 8.00 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=9.6 Hz), 7.31 (1H, d, J=8.4 Hz), 5.46 (2H, s), 4.96 (2H, s), 3.59 (3H, s); 13C NMR (CDCl3) δ 202.5, 162.4, 147.6, 137.1, 133.9, 122.9, 118.3, 115.6, 114.6, 95.3, 64.4, 57.2; FTIR (neat) 2926, 1738, 1258, 1078, 795 cm−1; MS (ESI) m/z calculated for (C13H10N2O3+H)+ 245, found 245; HRMS (ESI) m/z calculated for (C13H10N2O3+H)+ 245.0922, found 245.0914.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=O)[C:18]2=[O:25].FC1C=C2C(=CC=1)NC(=O)C2=O>>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[C:19](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:18]2=[O:25]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2cc(Br)ccc2-n2c1nc1ccccc1c2=O
Yield: 9 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-bromoisatin for 5-fluoroisatin gave the title compound in 9% yield: mp 288°-290.2° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (d, 1H) 8.44 (d, 1H) 8.06 (s, 1H) 8.04 (s, 1H) 7.82-7.96 (m, 2H) 7.66-7.76 (m, 1H); MS (M+H)+ 328.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][NH:18][CH3:19])[N:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:20]C1SC(NC)=CC=1>>[F:20][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][NH:18][CH3:19])[N:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CNCc1csc(NC(=O)NCc2ccc(Cl)s2)n1
Reactant: CNc1ccc(F)s1
Product: CNCc1csc(NC(=O)NCc2ccc(F)s2)n1

Procedure:
It was prepared following the same method of the preparation of Intermediate 29, starting from (5-fluoro-thiophen-2-yl)-methylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37]([OH:39])=O)[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:89][C@@H:90]([CH2:103][C:104]1[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=1)[CH2:91][CH2:92][C:93]1[CH:98]=[CH:97][C:96]([S:99]([OH:102])(=[O:101])=[O:100])=[CH:95][CH:94]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37](=[O:39])[NH:89][C@H:90]([CH2:91][CH2:92][C:93]1[CH:94]=[CH:95][C:96]([S:99]([OH:102])(=[O:100])=[O:101])=[CH:97][CH:98]=1)[CH2:103][C:104]1[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@H](CCc1ccc(S(=O)(=O)O)cc1)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](CCc1ccc(S(=O)(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 43 mg (0.06 mmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide in 1.9 ml of DMF were added 29 mg (0.07 mmol) of HATU and 33 μl (0.19 mmol) of Hünig's base. The reaction mixture was stirred at RT for 30 min and then admixed with 29 mg (0.07 mmol) of 4-[(3R)-3-amino-4-phenylbutyl]benzenesulphonic acid trifluoroacetate. After stirring overnight, the reaction mixture was purified by prep. HPLC. This gave 58 mg of a 45:55 mixture of the title compound and of the already deprotected amine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[CH2:35][N:36]=[C:37]=[O:38]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:37]([NH:36][CH2:35][C:34]4[CH:39]=[CH:40][CH:41]=[C:32]([CH3:31])[CH:33]=4)=[O:38])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1cccc(CN=C=O)c1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: Cc1cccc(CNC(=O)NC[C@H]2C[C@@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)c1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-methyl-benzyl)-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 3-methylbenzyl isocyanate (Aldrich, Buchs, Switzerland). Analytical HPLC: tR=7.45 min (Grad 2); ES-MS: m/eo=546.9.
Reaction SMILES: Cl.CO[CH:4](OC)[CH2:5]Cl.[C:9]([O:15]CC)(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[OH-].[Na+]>N1C=CC=CC=1.C(O)C.O>[CH3:13][C:11]1[O:12][CH:4]=[CH:5][C:10]=1[C:9]([OH:15])=[O:14]
Reactant: COC(CCl)OC
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1occc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a stirred solution of water (400 mL) and conc. hydrochloric acid (40 mL) is added chloroacetaldehyde-dimethylacetal (300 g) and brought to reflux. The homogenous solution was then added to a stirred cooled solution of ethyl acetoacetate (260 g. 2 mol) in pyridine (500 mL). This reaction mixture was allowed to stir overnight at ambient temperature. The lower layer of the reaction mixture was then removed and combined with the methylene chloride (2×100 mL) extract of the upper layer after dilution with an equal volume of water. The combined organics were washed with 1N HCl (200 mL), and evaporation of the solvent left the crude ester. Hydrolysis of this ester was accomplished by refluxing for 1 hour in ethanol (100 mL) and sodium hydroxide (50 g) in water (700 mL). The reaction mixture was then poured into water/ice (3 L) and acidified with hydrochloric acid to give a cream precipitate which was collected on a filter, washed with water and dried, to produce 180 g of 2-methyl-3-furoic acid, m.p. 105-106° C.
Reaction SMILES: O=[C:2]1[NH:7][CH2:6][C:5](=O)[N:4]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:3]12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:2]1[NH:7][CH2:6][CH2:5][N:4]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:3]12
Reactant: O=C1NCC(=O)N2CCCC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C1CCN2CCNC[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
(S)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (S)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14](OCC)=[O:15])=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1conc1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1conc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of ethyl 3-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (8.00 g) in tetrahydrofuran (150 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (6.46 g, yield 95%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 70–71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3cc(Cl)ccc23)CC1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3cc(Cl)ccc23)CC1

Procedure:
(25.4 mg, 72%); from 6-chloro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5b, 25 mg, 0.10 mmol) and benzoyl chloride (21.1 mg, 0.15 mmol), HRMS-FAB+ for C21H21ClN2O, calculated MH+ : 353.14206; found: 353.13873.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:23])#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:23])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(C(=O)OC)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), methyl 4-ethynyl-3-methylbenzoate (from the previous step) (1.0 eq.), bis(triphenyl-phosphine)palladium chloride (10 mol %), copper iodide (10 mol %), and triethylamine (5.0 eq.) in DMF (0.04 M) was stirred at 60° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give methyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)-3-methylbenzoate as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[NH:56]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:57]([C:65]([OH:67])=O)[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:56]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:57]([C:65]([NH:1][C@@H:2]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11])=[O:67])[CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1

Procedure:
Using 3.7 g Boc-D-Arg(Tos)-Tyr(Bzl)-OBzl, 1.40 g Boc-Phe-OH, 1.05 g HONB and 1.20 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(II).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[S:14][N:13]=[N:12][C:11]=2[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](Cl)(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([NH:17][C:15]([C:11]1[N:12]=[N:13][S:14][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:16])(=[O:20])[CH3:19]
Reactant: NC(=O)c1nnsc1Nc1ccccc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)c1nnsc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To an ice-cooled suspension of NaH (16 mg 60% in oil, 0.23 mmole) in 1.5 mL of DMF was added 0.5 mL of DMF solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid amide (50 mg, 0.23 mmole). The mixture was stirred at room temperature for 1 h, and then cooled in an ice bath. To the cooled solution was added acetyl chloride (18.6 mg, 0.24 mmole), resulting in the formation of a yellowish solution that was kept stirring at room temperature for 1.5 h. The reaction was then quenched with a mixture of 5 mL of saturated aqueous NH4Cl, 5 mL of saturated aqueous NaCl and 5 mL of EtOAc. The aqueous phase was extracted with EtOAc (2×6 mL). The combined organic layers were dried with Na2SO4, concentrated, and then loaded onto a preparative TLC plate, which was sequentially eluted with hexane-EtOAc (2:1) and EtOAc-acetone-H2O (4:1:0.15). The product (24 mg) was obtained as a yellowish solid. 1H NMR (ppm, in DMSO-d6): 12.84 (s, br., 1H), 7.79 (d, 2H), 7.64 (s, br., 1H), 7.53 (t, 2H), 7.40 (t, 1H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:7]([CH3:9])[CH3:8])([Cl:6])Cl)[CH3:3].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][CH:7]([Si:4]([CH:2]([CH3:1])[CH3:3])([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[Cl:6])[CH3:9]
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Reactant: CCCCCCCCO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCO[Si](Cl)(C(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Alternatively, di(2-propyl)octyloxychlorosilane was prepared as follows. To a 1000 ml three-neck round-bottom flask fitted with a stirrer, drying tube, thermometer and dropping funnel was added di(2-propyl)dichlorosilane (28.3 g, 153 mmol) and dry toluene (200 ml). The reaction mixture was then stirred and cooled to -5° C. A solution of dry octanol (10.0 g, 76 mmole) and dry pyridine (6.5 g, 82 mmole) in dry toluene (100 ml) was added dropwise for 60 minutes. The reaction mixture was suspended overnight at room temperature, filtered under a "nitrogen blanket" and fractionated.