Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:3][N:2]=1>C(O)C.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14][OH:15])=[CH:3][N:2]=1
Reactant: OCCC#Cc1cncc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: OCC/C=C/c1cncc2ccccc12
Reaction time: 5 h
Yield: 96.1 %

Procedure:
A solution of 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol in 35 mL of ethanol was hydrogenated over 0.35 g of 10% Pd/C at room temperature and atmospheric pressure for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated to yield 3.3 g of (E)-4-(4-isoquinolinyl)-3-buten-1-ol as an oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](=O)[CH2:4][C:5]([C:7]1[C:16](=[O:17])[NH:15][C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[C:8]=1[OH:18])=[O:6].Cl.[NH2:23][OH:24]>C(O)C>[F:1][C:2]([F:21])([F:20])[C:3](=[N:23][OH:24])[CH2:4][C:5]([C:7]1[C:16](=[O:17])[NH:15][C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[C:8]=1[OH:18])=[O:6]
Reactant: NO
Reactant: O=C(CC(=O)C(F)(F)F)c1c(O)c2nccnc2[nH]c1=O
Agent: Cl
Solvent: CCO
Product: O=C(CC(=NO)C(F)(F)F)c1c(O)c2nccnc2[nH]c1=O
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a suspension of 4,4,4-trifluoro-1-(8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-7-yl)-butane-1,3-dione (Example 6.3) (0.170 g) in ethanol (2 ml) was added hydroxylamine hydrochloride (0.050 g). The reaction mixture was heated to reflux for 4 hours and was then stored at ambient temperature for 16 hours. The solid was isolated by filtration and washed with ethanol, ethyl acetate, and diethyl ether and dried to give 4,4,4-trifluoro-1-(8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-7-yl)-butane-1,3-dione 3-oxime as a brown solid (0.078 g). 1H-NMR (400 MHz, d6-DMSO): 3.61 (d, 1H), 3.86 (d, 1H), 8.57 (d, 1H), 8.67 (d, 1H), 12.35 (s, 1H) ppm.
Reaction SMILES: [OH:1][C@:2]([CH3:18])([C:16]#[CH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(N(CC)CC)C>[C:19]([O:1][C@:2]([CH3:18])([C:16]#[CH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Solvent: CCN(CC)CC
Product: C#C[C@](C)(CCC1=C(C)C(=O)C(C)=C(C)C1=O)OC(C)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1.23 g (5 mmol) of (S)-2-[3-hydroxy-3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione ([α]D25 +11.3° CH2Cl2), 1.05 mL of triethylamine, 120 mg of 4-N,N-dimethylamino pyridine, and 0.6 mL of acetic anhydride in 8 mL of CH2CL2 was stirred at 25° C. under argon for 17 h. It was diluted with CH2CL2 (70 mL), washed with 1.0N HCl, saturated NaHCO3 solution, water and dried over MgSO4. The crude material (1.6 g) was purified by flash chromatography on silica gol (50 g, 230-400 mesh). Elution with ether:petroleum ether (3:17) gave 1.47 g of (S)-2-[3-(acetyloxy)-3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione as a yellow oil, [α]D25 -21.42° (c, 0.994, CH2Cl2).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[CH:14][C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[CH:6][C:5]=1[N+:16]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][CH2+:38]1SC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[C:41](=[O:42])[C:40](=[C:43]2[N:47]([CH3:48])[C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:44]2)[S:39][C:38]1=[N:16][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH:14]=[CH:15][C:4]=1[NH:3][CH2:1][CH3:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)COC)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.99 (1H, s), 7.39-7.44 (3H, m), 7.17-7.28 (5H, m), 7.05-7.11 (2H, m), 694 (1H, d), 6.50 (1H, d), 5.08 (2H, s), 3.92 (2H, s), 3.66 (3H, s), 3.41 (3H, s), 2.91 (2H, q), 0.96 (3H, t); MS(ESI): 560 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]2[N:20]([CH2:21][C:22]3[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=3)[N:19]=[C:18]([CH3:28])[CH:17]=2)[C@H:13]([C:29]([O:31]C)=[O:30])[CH2:12]1)(=[O:10])=[O:9].[OH-].[Li+:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]2[N:20]([CH2:21][C:22]3[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=3)[N:19]=[C:18]([CH3:28])[CH:17]=2)[C@H:13]([C:29]([O-:31])=[O:30])[CH2:12]1)(=[O:9])=[O:10].[Li+:34]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1Cc1cncn1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)[O-])n(Cc2cncn2C)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxylate was saponified in the presence of lithium hydroxide to give the title compound as brown solid which was used in the next step without further purification. MS (ESI): m/z=462.1 [M−H]−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[O:32][CH2:33][C@@H:34]1[CH2:36][O:35]1>>[OH:35][C@H:34]([CH2:33][O:32][C:23]1[CH:24]=[CH:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=1)[CH2:36][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc2cc(OC[C@@H]3CO3)ccc2c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc4ccccc4c3)CC1)O2

Procedure:
Compound 221 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(2-naphthyloxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=164-167° C., (DMSO-d6) δ: 7.91-7.87 (m, 1H), 7.84-7.78 (m, 5H), 7.6-7.52 (m, 1H), 7.48-7.4 (m, 1H), 7.38-7.3 (m, 2H), 7.2-7.14 (m, 1H), 5.0-4.93 (m, 1H), 4.2-3.97 (m, 3H), 3.07 (s, 2H), 2.93-2.76 (m, 2H), 2.63-2.4 (m, 4H), 2.06-1.93 (m, 2H), 1.9-1.78 (m, 2H); LCMS=502 [M+H].
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)=[N+:2]=[N-:3].[BH4-].[Na+]>CO>[N:1]([CH:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NC1CCC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Azido-cyclopentanone (about 7.2 g, 57.6 mmol) in methanol (250 mL) was added sodium borohydride (11 g, 288 mmol) in five portions at 0° C., then the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic solution (TLC showed one spot) was concentrated and the residue was used for the next step. 1H NMR (400 MHz, CDCl3) δ: 4.25-4.30 (m, 1H), 3.95-3.80 (m, 6H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47]CC)=[O:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:35])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CCCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)NCCCC(=O)O)cc2)cc1

Procedure:
The product from Example 95C and ethyl 4-aminobutyrate hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.69-12.36 (br.s, 1 H), 8.94 (s, 1 H), 8.09 (t, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.96 (m, 6 H), 6.83 (d, 2 H), 4.43 (s, 2 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 3.15 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.20 (t, 2 H), 1.66 (m, 2H); MS (ESI+) m/z 632 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]3)[C:11]([NH:19][CH3:20])=[N:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([I:28])[CH:30]=4)[C@@H:14]([CH3:18])[CH2:13]3)[C:11]([NH:19][CH3:20])=[N:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(I)c1
Reactant: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN[C@@H](C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN(Cc1cccc(I)c1)[C@@H](C)C2
Reaction time: 8 h

Procedure:
(5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (250 mg, 0.86 mmol) from step 2 above was dissolved in DMSO (8.0 mL). The flask was charged with K2CO3 (594 mg, 4.30 mmol) and 3-iodo-benzylbromide (255 mg, 0.86 mmol). The mixture was then sealed with a septum and placed in 50° C. oil bath and allowed to stir overnight. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic layers were washed with aqueous LiCl (three times), followed by brine and then dried over Na2SO4. Solvent removal under reduced pressure gave crude product. Purification over silica via automated flash chromatography (0 to 20% MeOH/CH2Cl2 over 20 min.) gave after solvent removal the product as a white solid: LCMS [M+H]=507.3
Reaction SMILES: [C:1]([O:9][CH2:10][C:11](=[O:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](O)[CH2:16][CH2:17][OH:18].C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.O>[C:1]([O:9][CH2:10][C:11]1([CH2:12][OH:13])[O:18][CH2:17][CH2:16][CH2:15][O:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CO)COC(=O)c1ccccc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: O
Product: O=C(OCC1(CO)OCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the mixture (0.5 g) containing 3-hydroxy-2-oxopropyl benzoate, 1,3-propanediol (0.932 ml, 12.9 mmol), triethyl orthoformate (0.428 ml, 2.58 mmol), and p-toluenesulfonic acid monohydrate (44.5 mg, 0.234 mmol) was stirred at room temperature for 4 days. Another mixture consisting of the mixture (4 g) containing 3-hydroxy-2-oxopropyl benzoate, 1,3-propanediol (7.46 ml, 103 mmol), triethyl orthoformate (3.42 ml, 20.6 mmol), and p-toluenesulfonic acid monohydrate (356 mg, 1.87 mmol) was stirred at 40° C. overnight. Two reaction mixtures were combined, water and ethyl acetate were added, and the organic layer was taken out. The organic layer was dried over magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (2/1) and toluene and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=3/2) to obtain the title compound (4.2 g).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22](C)(C)[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:13]([CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)[CH2:30][CH2:31]1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: Sc1ccccc1
Product: C[C@H]1CC[C@H](N(CCCSc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[N:15][C:16]1[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH:25]([CH3:27])[CH3:26])([CH3:3])[CH3:2].[CH2:28]([N:30]([CH2:32][CH3:33])[OH:31])[CH3:29].[OH-].[Na+]>C1COCC1>[CH:22]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:25]([CH3:27])[CH3:26])[C:16]=1[NH:15][C:14](=[N:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])[O:31][N:30]([CH2:32][CH3:33])[CH2:28][CH3:29])([CH3:24])[CH3:23]
Reactant: CCN(O)CC
Reactant: CC(C)c1cccc(C(C)C)c1N=C=Nc1c(C(C)C)cccc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)OC(=Nc1c(C(C)C)cccc1C(C)C)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.3 %

Procedure:
To a solution of bis(2,6-diisopropylphenyl)carbodiimide (4.35 g, 12 mmol) and N,N-diethylhydroxylamine (1.6 g, 18 mmol) in THF (20 ml) is added finely powdered NaOH (48 mg) and the mixture is stirred at room temperature for 22 hours. The reaction mixture is then filtered and the filtrate is evaporated on the rotary evaporator below 45° C. The residue is recrystallized twice from acetonitrile to afford 1.75 g of the title compound as a white solid, mp. 113-116° C.
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:13](O)=[O:14]>CCOCC>[CH:13]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[CH2:1])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:14]
Reactant: O=CO
Reactant: C=C(CCCCO)CC(C)(C)C
Solvent: CCOCC
Product: C=C(CCCCOC=O)CC(C)(C)C
Reaction time: 24 h

Procedure:
20 mM of 5-methylene-7,7-dimethyloctanol were esterified with 6 ml of concentrated formic acid. The reaction took place at room temperature, under nitrogen and by mixing the ingredients under stirring for 24 h. The mixture was taken up with ether, washed with 2N NaOH, then with water until neutrality. The desired product was obtained after drying, concentration and bulb distillation under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.C(Cl)Cl.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1)N1CCOCC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c2ccccc12

Procedure:
A solution of N-(4-((4-nitronaphthalen-1-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide (900 mg, 2.3 mmol) in a mixture of MeOH (140 mL), DCM (140 mL) and AcOH (4 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 55 mm, 10% Pt—C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo and the residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic phase was separated and was washed with brine (20 mL), and then dried and evaporated in vacuo to afford the title compound, Intermediate D5, as a brown solid (0.78 g, 90%); Rt 3.65 min (Method 1 basic); m/z 365 (M+H)+ (ES+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]#[N:14])(=[O:3])[CH3:2].C(N(CC)CC)C.[SH2:22]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[S:22])[NH2:14])(=[O:3])[CH3:2]
Reactant: S
Reactant: CC(=O)N1c2ccccc2CC1C#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2CC1C(N)=S
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (0.00988 mol) and Triethylamine (0.0197 mol) in pyridine (50 ml) was treated with hydrogen sulfide (gas) at room temperature via a bubbler for 2 hours and the resultant saturated reaction mixture was closed and allowed to set for 16 hours. The reaction mixture was poured into 200 ml of an ice water slurry. A voluminous precipitate formed. The mixture was recooled in an ice bath and the precipitate was collected by suction filtration, washed with cold water, and air dried, yielding 1.62 g of 1-acetyl-2,3-dihydro-1H-indole-2carbothioamide (intermediate 13, mp. 194–195° C.).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([N:17]([CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[N:17]([CH2:42][CH2:43][N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)[C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[CH:10][C:11]=12
Reactant: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(N(CCN2CCOCC2)c2ccnc3[nH]ncc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 112.9 %

Procedure:
N-(4-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(2-morpholinoethyl)amino)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (0.015 g, 0.02165 mmol) was dissolved in TFA (0.1668 ml, 2.165 mmol) and stirred at 60° C. for 18 hours. Excess TFA was evaporated, and the crude product was then resuspended in toluene and reconcentrated to remove trace TFA. The crude solid was then partitioned between EtOAc and NaHCO3. The organic layer was separated and dried over sodium sulfate. After filtration to remove sodium sulfate and concentration, the residual crude solid was taken up in a small amount of DCM and treated with 2N HCl in ether. The suspension was evaporated to dryness to give 14 mg (95%) of product as a brown solid. LRMS (apci pos): 573.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[NH3:13]>>[NH2:13][CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: N
Reactant: CCO[Si](C)(CCCCl)OCC
Product: CCO[Si](C)(CCCN)OCC

Procedure:
According to Example 1, 6.6 kg (31.1 mol) 3-chloropropylmethyldiethoxysilane are reacted with 24 kg (1412 mol) ammonia, excess ammonia is removed by pressure distillation and flash processes and the 3-aminopropylmethyldiethoxysilane that is formed is isolated by filtration and vacuum distillation.
Reaction SMILES: CC1C(OC2C=CC=C(CCC)C=2)=NC=C([N+]([O-])=O)C=1.[CH3:21][C:22]1[C:23]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=2)=[N:24][CH:25]=[C:26]([N+:28]([O-])=O)[CH:27]=1>>[NH2:28][C:26]1[CH:27]=[C:22]([CH3:21])[C:23]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=2)=[N:24][CH:25]=1
Reactant: CCOc1cccc(Oc2ncc([N+](=O)[O-])cc2C)c1
Agent: CCCc1cccc(Oc2ncc([N+](=O)[O-])cc2C)c1
Product: CCOc1cccc(Oc2ncc(N)cc2C)c1

Procedure:
The title compound was prepared in a similar way with respect to Intermediate 26 replacing 3-methyl-5-nitro-2-{[3-(2-methylethyl)phenyl]oxy}-pyridine (Intermediate 24) with 3-methyl-5-nitro-2-{[3-(ethyloxy)phenyl]oxy}-pyridine (Intermediate 25).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:35]#[C:36][CH2:37][OH:38])=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]>CCOC(C)=O.O=[Pt]=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][OH:38])=[C:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxyprop-1-ynyl)thiazole-4-carboxylate (38D) (2.0 g, 3.96 mmol) in EtOAc (20 mL) was added PtO2 (240 mg, 1.1 mmol). The mixture was stirred at rt under hydrogen (balloon) overnight. The mixture was then filtered and the filtrate was concentrated under reduced pressure to provide the desired product 38E: 1H NMR (300 MHz, CDCl3) δ ppm 8.30 (1H, m), 7.71 (1H, d), 7.59 (1H, m), 7.49 (1H, m), 7.35 (3H, m), 6.00 (2H, s), 5.14 (2H, s), 3.95 (2H, m), 3.75 (2H, t), 3.63 (2H, m), 3.17 (2H, t), 3.07 (2H, t), 2.40 (1H, t), 1.89 (2H, m), 1.58 (9H, d), 0.98 (2H, t), 0.01 (9H, m). MS (ESI(+)): m/z 681 (M+H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5])[CH3:3].[ClH:25].CCOCC>O1CCOCC1>[NH2:1][C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:5])[CH3:3].[ClH:25]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@H](N)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
3.4 g of Boc-(D)Ala-Gly-OBzl are dissolved in 50 ml of dioxane containing HCl and left to stand for one hour. The volume of the solution is reduced under vacuum and an excess of ether added. The precipitated salt is filtered off, dried and used as such for the coupling reaction.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23]C(=O)C)=[C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32]C(=O)C)[CH:15]=[CH:14][C:11]=1[CH:12]=O)(=O)C.C(O)(=O)[CH2:37][C:38]([OH:40])=[O:39].N1CCCCC1.[OH-].[K+].Cl>O.N1C=CC=CC=1>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:15]=[CH:14][C:11]=1[CH:12]=[CH:37][C:38]([OH:40])=[O:39]
Reactant: O=C(O)CC(=O)O
Reactant: CC(=O)OCCCCOc1ccc(C=O)c(OCCCCOC(C)=O)c1OCCCCOC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(OCCCCO)c(OCCCCO)c1OCCCCO
Temperature: 110 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
Into a three-neck flask, 2,3,4-tri(4-acetyloxy-butyloxy)benzaldehyde (40.0 g), malonic acid (10.6 g), piperidine (1 ml) and 100 mL of pyridine were added and stirred at 110° C. for 5 hours. After cooling, water (500 ml) and potassium hydroxide (26.0 g) were added and stirred at 60° C. for 2 hours. After cooling, concentrated hydrochloric acid was added until the reaction solution became acidic, and the resulting reaction solution was extracted with ethyl acetate and washed with water. The extract was concentrated and then purified by column chromatography to obtain the titled compound (30.1 g). Yield: 90%.