Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=1>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[CH:15])=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OC2CCCCO2)cc1
Solvent: CO
Product: C#Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(9.3 g, 160 mmol) was added to a stirred solution of 2 (22.6 g, 80 mmol) in MeOH (150 ml). The reaction mixture was stirred at room temperature for about 4 hours. After the reaction finished (GC shows no starting material remaining), the solvent was removed under reduced pressure on a rotary evaporator. The residue was purified by column chromatography on silica gel (petroleum ether-ethyl acetate=9:1) to give a pale yellow crystals of 3. Yield 15.7 g(97%); mp 65° C., δH(CDCl3; 300 MHz): 7.42(d, J=8.7, 2H, Ar—H), 7.00(d, J=8.7, 2H, Ar—H), 5.43(t, J=3.2, 1H, OCHO), 3.87(m, 1H, THP, 3.60(m, 1H, THP), 2.99(s, 1H, C═C—H), 1.96˜1.56(m, 6H, THP).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1.C(O)C>O1CCCC1>[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(F)nc3F)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(F)nc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Lithium hydroxide (0.106 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.24 g) and diethyl [(3S,8aR)-3-(2,6-difluoropyridin-3-yl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.0 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.42 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:18][O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])(=[O:12])=[O:11])=[C:5]([CH3:28])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:11])=[C:5]([CH3:28])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCC[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCC[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)-pyrrolidin-2-yl)methoxy)acetate (1 eq.) in dichloromethane (10 ml/mmol) was added trifluoroacetic acid (2 ml/mmol) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 2 h. The solvent was evaporated off and it was dried under vacuum to remove traces of trifluoroacetic acid. The crude product was used directly for the next step. Yield: quantitative.
Reaction SMILES: C(OC(C)(C)C)(=O)C.[Li].C(O)(C(F)(F)F)=O.C([C:21](C(=O)C)([CH:25]([OH:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([OH:24])=[O:23])(C)(C)C>>[OH:33][CH:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCCCCC(O)C(C(C)=O)(C(=O)O)C(C)(C)C
Agent: [Li]
Solvent: CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC(O)CC(=O)O

Procedure:
Synthesis of analogs (18), (20) and (21) proceeded by a shortened piperidine deblock of Fmoc-OBzl-D-Glu (Schiffler, R. J., et al., Amer. Med. Assoc. 251:2983 (1984)). The reduction of deblock from 20 to 5 minutes was necessary to prevent the cyclization (Hubert, A. J., et al., Helv. Chim. Acta 46:1429-1445 (1963)) of OBzl-D-Glu to pyroglutamic acid. The orthoganol Boc/Fmoc protection scheme allowed the selective removal of the base labile Fmoc group, while maintaining the base insensitive Boc protection on the L-Ile. The synthesis was continued by coupling of Fmoc-L-Leu (Keierszenbaum, F., Trop. Med. Parasit, Mansfield ed., Marcel Dekker, New York (1984)) in the usual manner (DCC/HOBT) which was followed by piperidine-catalyzed Fmoc deprotection (20 minutes) and final acylation with either (-)-D-3-hydroxydecanoic acid (-), structure (23) (for analogs (18) and (20)), or decanoic acid (for analog (21)). Coupling of D-3-hydroxydecanoic acid was as the Pfp ester (24), with the 3-hydroxyl group unprotected. The acid was obtained by (-)-cinchonidine resolution (Cartwright, N.J., Biochem. J. 67:663-669 (1957)) of synthetic (±)-3-hydroxydecanoic acid [(35)-(12)]. The (±)-3-hydroxydecanoic acid itself (mp 55°-56° C.; 57° C.) was synthesized by the aldol condensation of lithium tert butyl acetate (Rathke, M. W., et al., J. Amer. Chem. Soc. 95:3050-3051 (1973)) with n-octyl aldehyde, followed by TFA hydrolysis of the resulting (±)-tert butyl acetyl-3-hydroxydecanoic acid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:53][OH:54].[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:53][O:54][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reactant: CO
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.192 mmol), Cu(I)I (0.0365 g, 0.192 mmol), 1,10-phenanthroline (0.0346 g, 0.192 mmol), methanol (0.389 mL, 9.59 mmol) and KF on Al2O3 (40%; 0.195 g, 1.34 mmol) in toluene (4 mL) was stirred at 110° C. for 20 hours. The reaction was cooled to room temperature. Ethyl acetate (10 mL) was then added, and the reaction mixture was filtered through a pad of celite. The filtrate was concentrated to dryness. The resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(3-methoxy-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.098 g, 96%) as a solid. MS APCI (+) m/z 530.4 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.06 (s, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.20 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.38 (s, 2H), 3.98 (s, 3H), 3.71 (s, 3H), 3.29 (m, 4H), 2.94 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: ClCC([NH:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[C:22]([N:23]=2)=[CH:21][CH:20]=[C:19]([C:24]2([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:26][CH2:25]2)[N:18]=3)=[C:11]([F:33])[CH:10]=1)([CH3:8])[CH3:7])=O.NC(N)=S>C(O)C.C(O)(=O)C.C(Cl)Cl>[F:33][C:11]1[CH:10]=[C:9]([C:6]([NH2:5])([CH3:7])[CH3:8])[CH:14]=[CH:13][C:12]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: CC(C)(NC(=O)CCl)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: NC(N)=S
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
To a solution of 2-chloro-N-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-yl)acetamide (0.51 g, 1.0 mmol) in ethanol (10 mL) and acetic acid (2 mL) was added thiourea (0.12 g, 1.58 mmol). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 1% to 10% MeOH/CH2Cl2 afforded a crude crop of the desired product. Trituration with CH2Cl2 afforded 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-propan-2-amine as a white amorphous solid. MS (ESI) m/z: Calculated: 403.2; Observed: 404.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:5]2=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26]
Reactant: CCCC(C(=O)OC)c1c(C)nc2scc(-c3ccccc3)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2scc(-c3ccccc3)c2c1-c1ccc(C)cc1
Temperature: 60 °C
Yield: 19.9 %

Procedure:
To a solution of methyl 2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.27 g; 0638 mmol) in methanol (6.3 mL) was added a solution of sodium hydroxide 5 N (1.3 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.052 g (20%) of the title compound as a light yellow solid.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:23][C:24]([C:26]2([NH:41]C(=O)OC(C)(C)C)[CH2:31][CH2:30][N:29]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>>[NH2:41][C:26]1([C:24]([NH:23][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[O:25])[CH2:27][CH2:28][N:29]([C:32]2[C:33]3[CH:40]=[CH:39][NH:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCNS(C)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CS(=O)(=O)NCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
HCl (4M) in 1,4-Dioxane (1.615 mL, 6.46 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 117) (261 mg, 0.43 mmol), The resulting suspension was stirred at 20° C. for 1 hour. No reaction. TFA (1 mL) was then added to the reaction and stirred for 16 hours. The reaction was vacuumed to dryness and was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3/MeOH and pure fractions were evaporated to dryness to afford crude material. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing [AP-HPLC Buffer]) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(methylsulfonamido)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (142 mg, 65.2%) as a white solid.
Reaction SMILES: I.[PH2](O)=O.[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)(=O)C.O>[CH3:5][C:6]1[NH:7][C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1c(C)[nH]c(Cc2ccccc2)c1C
Reaction time: 0.17 h

Procedure:
A solution of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of 50% hypophosphorous acid containing 548 mg of 2,4-dimethyl-3acetyl pyrrole was stirred magnetically while a solution of 0.6 ml of benzaldehyde in 5 ml of acetic anhydride was slowly added over 20 mins. The solution was stirred for 10 mins, then poured into water. The crude product which separated was recrystallized from acetone (thimble) as nearly colourless irregular plates (85%, m.p. 165.5°-167° C. after a partial change to prismatic rods above 165° C. Anal. Cal. for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.22; H, 7.50; N, 6.18.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH:27]([CH3:29])[CH3:28])[C:23](=[O:26])[NH:24][CH2:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]([CH3:30])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH:27]([CH3:28])[CH3:29])[C:23](=[O:26])[N:24]=[CH:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCC(N(C)C)CC4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1c(=O)ncc2cnc(Nc3ccc(N4CCC(N(C)C)CC4)cc3)nc21
Reaction time: 48 h
Yield: 19 %

Procedure:
Prepared from 200 mg (0.31 mmol) of 7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}-1-isopropyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 211 mg (1.88 mmol) of potassium tert-butoxide in 7 mL of tetrahydrofuran. The reaction mixture is stirred for 48 hours, and the workup is done as described in the general procedure, then the reaction is repeated for 72 hours. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 24 mg (18%) of the title compound:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[C:12]([S:31][CH2:32][CH2:33][C:34](O)=[O:35])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(SCCC(Cl)=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:62][NH:63][C:64]1[S:65][C:66]([C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)=[N:67][N:68]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl.C(=O)(O)[O-].[Na+]>[CH3:62][N:63]([C:64]1[S:65][C:66]([C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)=[N:67][N:68]=1)[C:34](=[O:35])[CH2:33][CH2:32][S:31][C:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNc1nnc(-c2cccnc2)s1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C(=O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Reaction time: 17 h
Yield: 86.1 %

Procedure:
Oxalyl chloride (380 μL, 4.3 mmol, 1.5 equiv) and N,N-dimethylformamide (11 μL, 0.14 mmol, 0.05 equiv) were sequentially added to a stirred suspension of 3-(tritylthio)propanoic acid (1.0 g, 2.9 mmol, 1.0 equiv) in toluene (10 mL) at 23° C. The resulting bubbling white suspension was stirred at 23° C. for 17 h. The reaction mixture was concentrated by rotary evaporation. A portion of the resulting product, 3-(tritylthio)propanoyl chloride (400 mg, 1.1 mmol, 1.1 equiv), was added to a stirred suspension of N-methyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-2-amine (190 mg, 1.0 mmol, 1.0 equiv) and 4-dimethylaminopyridine (150 mg, 1.2 mmol, 1.2 equiv) in dichloromethane (3.0 mL) at 23° C. The resulting yellow solution was stirred at 23° C. for 15 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a white foam (450 mg, 87%): mp 60-75° C.; IR (KBr thin film) 3438 (w), 3024 (w), 2909 (w), 2742 (w), 2649 (w), 2565 (w), 1701 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 9.12 (d, J=2 Hz, 1H), 8.67 (dd, J=5, 2 Hz, 1H), 8.25 (dt, J=8, 2 Hz, 1H), 7.18-7.50 (m, 16H), 3.58 (s, 3H), 2.73 (t, J=7 Hz, 2H), 2.34 (t, J=7 Hz, 2H); ESIMS m/z 523 ([M+H]+).
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:15][C:16](=[O:41])[C@@H:17]2[CH2:21][C@@H:20]([NH:22][C:23](=[O:33])[CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:19][N:18]2C(OC(C)(C)C)=O)[CH:3]=1>O1CCOCC1.CO>[ClH:1].[ClH:1].[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]([CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:15][C:16](=[O:41])[C@@H:17]2[CH2:21][C@@H:20]([NH:22][C:23](=[O:33])[CH2:24][NH2:25])[CH2:19][NH:18]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N[C@H](CCc2ccccc2)C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)N[C@H](CCc2ccccc2)C(=O)Nc2cnc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 4 N hydrogen chloride in 1,4-dioxane (10 mL) was added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-prolyl-D-homophenylalanine 3-quinolylamide (C, 162 mg) in methanol (10 mL) at 0° C. After stirring at 0° C. for 5 min and at room temperature for 3 hr, the solution was concentrated in vacuo. The residue was purified by HPLC(Shiseido, Capcell Pak C18 UG120, 3 cm×25 cm, 0.02 N hydrochloric acid: methanol=65:35, v/v) and freeze-dried from water to afford the title compound (90 mg) as a pale yellow powder: 1H NMR (400 MHz, D2O) δ 2.18-2.43 (m, 3H), 2.43-2.57 (m, 1H), 2.74-2.96 (m, 2H), 3.40 (dd, J=12.2,4.4 Hz, 1H), 3.76-3.87 (m, 3H), 4.45-4.60 (m, 2H), 4.61-4.73 (m, 1H), 7.01-7.17 (m, 1H), 7.17-7.31 (m, 4H), 7.86 (t, J=7.8 Hz, 1H), 8.00 (t, J=7.8 Hz, 1H), 8.04-8.19 (m, 2H), 8.81 (s, 1H), and 9.15 (s, 1H); IR (KBr) 3388, 3205, 3037, 1685, 1681, 1610, 1571, 1552, 1496, 1486, and 1454 cm−1; mass spectrum (EI+) m/e 474 (M+); (FAB+) m/e 475 (M+1); Anal. Calcd for 26H30N6O3.3HCl.3H2O: C, 48.95; H, 6.16; N, 13.17. Found: C, 49.16; H, 5.90; N, 13.15.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:24])[C:5]1[CH:6]=[C:7]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]([O:22]C)=[O:21])=[CH:12]2)[CH:8]=[CH:9][CH:10]=1.Cl>O1CCCC1>[CH3:3][N:4]([CH3:24])[C:5]1[CH:6]=[C:7]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]([OH:22])=[O:21])=[CH:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cn(-c2cccc(N(C)C)c2)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)c1cccc(-n2cc(C(=O)O)c3cccnc32)c1

Procedure:
1.6 cm3 of a 10N sodium hydroxide solution were added to methyl 1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate in 15 cm3 of tetrahydrofuran. After stirring at reflux of the solvent for 48 h, the reaction mixture was acidified with 2 cm3 of 10N hydrochloric acid and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(3-(dimethylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, characterized by LC/MS (m/z 282 [MH]+), which was used directly in the following stage.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].I[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: Ic1cccnc1
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Temperature: 120 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
1,1-Dimethylethyl (2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 55) (150 mg, 0.351 mmol), 3-iodopyridine (144 mg, 0.702 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (27.6 mg, 0.070 mmol), tris(dibenzylideneacetone)dipalladium(0) (32.1 mg, 0.035 mmol) and sodium tert-butoxide (67.4 mg, 0.702 mmol) were dissolved in 1,4-dioxane (4 mL) and the resulting mixture was stirred at 100° C. under nitrogen for 20 h, at 120° C. for 16 h, then cooled to room temperature and concentrated in vacuovacuo. The residue was partitioned between DCM and a saturated NaHCO3 aqueous solution and the layers were separated using a hydrophobic frit. The organic phase was concentrated in vacuovacuo. Purification of the residue by SP4 using a 50 G silica cartridge (gradient:0.5 to 10% (2M NH3 in MeOH) in DCM) gave 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (84 mg, 0.166 mmol, 47.4% yield).