Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[C:9](Cl)(=[O:11])[CH3:10]>C1COCC1.C(OCC)C.C([O-])([O-])=O.[K+].[K+]>[OH:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][C:9](=[O:11])[CH3:10]
Reactant: OCCCCO
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)OCCCCO
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
1,4-Butanediol (0.90 ml, 10.16 mmol) was added to a stirred suspension of NaH (246 mg, 10.25 mmol) in THF (20 ml) at room temperature and stirred for 30 minutes. Acetyl chloride (0.70 mL, 9.84 mmol) was then added to the thick white slurry. Following 45 minutes of stirring, the solution was diluted with diethyl ether (30 mL) and 10 w/v % K2CO3 (aq). The phases were separated and the organic phase washed with 10% K2CO3 (1×15 mL) and brine (1×15 mL). The combined aqueous phase was extracted with diethyl ether (1×30 mL). The organic phase was dried (MgSO4) and concentrated to afford 933 mg crude product as a colourless liquid. Purification by column chromatography (25 g silica, 2:1 hexanes:ethyl acetate) afforded 686 mg of acetic acid 4-hydroxy-butyl ester (51%). 1H NMR (CDCl3) δ 1.58-1.77 (m, 4H), 2.05 (s, 3H), 3.68 (t, 2H, J=6.1 Hz), 4.10 (t, 2H, J=6.4 Hz).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1N=C2N=CN(C3C=CC(C)=CC=3)C2=CC=1)C1C=CC=CC=1>>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(-n2cnc3ccc(OCc4ccccc4)nc32)cc1
Agent: Cc1ccc(-n2cnc3nc(OCc4ccccc4)ccc32)cc1
Product: Cc1ccc(-n2cnc3ccc(O)nc32)cc1

Procedure:
From the mixture of 5-(benzyloxy)-3-p-tolyl-3H-imidazo[4,5-b]pyridine and 5-(benzyloxy)-1-p-tolyl-1H-imidazo[4,5-b]pyridine, the benzyl group was removed as described in Example 1.11, Step B. Purification by preparative HPLC gave the title compound as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 2.41 (s, 3H), 6.70 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.6 Hz, 1H), 8.43 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([CH:14]=[O:15])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:15][CH2:14][C@H:12]1[CH2:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11]1
Reactant: O=C[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OC[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In a 50 mL flask with cis-3-benzyloxymethyl-cyclobutanecarbaldehyde (73 mg, 0.36 mmol) inside, dry CH2Cl2 7 mL was added under argon to give a colorless solution. Then this was cooled to −78° C., DIBAL-H (1.0 M in hexane, 0.7 mL, 0.72 mmol) was added drop by drop. This was left stirring at −78° C. and after 3 hr, the reaction was quenched with dry MeOH 0.2 mL. The reaction mixture was allowed to warm up to RT gradually. After 1.5 hr, 2 mL Rochelle salt was added and the mixture was stirred vigorously for overnight. Then the organic phase was separated and washed with brine, dried over MgSO4 and concentrated. Purification by silica gel flash chromatography (Hexane: EtOAc=3:1) yielded cis-1-hydroxymethyl-3-benzyloxymethyl-cyclobutane as a colorless oil (54 mg, 73.4%, Rf=0.17 (Hexane: EtOAc=3:1)). 1H NMR (CDCl3, 300 MHz): δ 1.48-1.61 (m, 2H), 2.10-2.20 (m, 2H), 2.40-2.55 (m, 2H), 3.39-3.41 (d, J=8.0, 2H), 3.54-3.56 (d, J=8.0, 2H), 4.51 (s, 2H), 7.20-7.40 (m, 5H).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[C:9]([C:10](=[O:12])[CH3:11])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:17]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(=CN(C)C)C(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A stirred mixture of benzoylacetone (16.2 g) and dimethylformamide dimethylacetal (16.2 ml) was heated on an oil bath at 80° C. for 40 minutes. Volatile materials were removed under vacuum and the residue was crystallised from ether to give 2-(dimethylaminomethylene)-1-phenyl-1,3-butanedione (mp 81°-83° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]2[NH:22][N:21]=[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][N:27]=[C:26]4[C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[N:19]=2)[CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]2[NH:22][N:21]=[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][N:27]=[C:26]4[C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[N:19]=2)[CH2:13]1
Reactant: c1cc(-c2n[nH]c3ccc(-c4n[nH]c([C@@H]5CCCNC5)n4)cc23)ccn1
Reactant: COc1cccc(F)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(F)c1CN1CCC[C@@H](c2nc(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n[nH]2)C1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
Added 2-Fluoro-6-methoxy benzaldehyde (69 mg, 0.44 mmol) to a mixture of (R)-5-(5-(piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole (96 mg, 0.277 mmol) and sodium triacetoxy borohydride (176 mg, 0.833 mmol) in MeOH (8 ml) at room temperature. After stirred for 30 minutes, the solvent was evaporated. Diluted with EtOAc (150 ml), washed with H2O (50 ml), dried (Na2SO4) and concentrated. Crude product was purified on silica gel eluting with 5% v/v MeOH/CH2Cl2 to yield (R)-5-(5-(1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole as a white solid (54 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[O:51]1[CH2:56][CH2:55][N:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:60]6[CH2:61][CH2:62][CH:57]([N:54]7[CH2:55][CH2:56][O:51][CH2:52][CH2:53]7)[CH2:58][CH2:59]6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCC(N5CCOCC5)CC4)cc3F)cn2)cc1
Yield: 138.9 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 4-morpholinopiperidine (40.2 mg, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-(4-morpholin-4-yl-piperidin-1-yl)-methanone as a brown solid (136 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-308) as a yellow powder (61.8 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CN(C=O)C>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH:4][S:15]([CH3:14])(=[O:17])=[O:16])=[C:2]([Br:1])[CH:8]=1)([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Commercially available 2-bromo-4-nitroaniline (10.0 g, 46.07 mmol) was dissolved in DMF (250 mL) and NaH (60% in oil dispersion; 3.7 g, 92.15 mmol) added portion wise at 0° C. After 15 minutes, methanesulfonyl chloride (10.7 mL, 138.23 mmol) was added and the reaction was stirred overnight at ambient temperature. The reaction was quenched with 1M citric acid (100 mL) and extracted with ethyl acetate (3x). The combined extracts were washed with brine (2x), dried (MgSO4), filtered and concentrated in vacuo to yield a red oil that was purified by flash chromatography (silica gel; 20% EtOAc/Hexane) to afford the title compound as a yellow solid which was recrystallyzed from ether/hexanes. mp 148°-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.24 (s, 3H), 7.70 (d; J=9 Hz; 1H), 8.23 (dd; J=9,3 Hz; 1H), 8.49 (d; J=3 Hz; 1H), 9.85 (br. s., 1H). MS (DCI-NH3) m/z 312 (M+NH4)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([NH:44][CH:42]([CH3:43])[CH2:41][C:39]2[O:40][C:36]([C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)=[CH:37][CH:38]=2)=[O:12])[NH:8][N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(N)Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1)NC(=O)c1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
5-Tert-butyl-2H-pyrazole-3-carboxylic acid (94 mg; 0.55 mmol) was dissolved in DCM:DMF (4:1, 5 ml). DCC (172 mg; 0.83 mmol) was added. 1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-amine (149 mg; 0.55 mmol) was dissolved in 2 ml of DCM and TEA (77 μl, 0.55 mmol) and the resulting solution was added to the reaction mixture. The reaction mixture was stirred overnight at RT. Then DCM (50 ml) was added and organic phase was washed with water (2×30 ml). The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, 1st column silica, eluent: 7.5-100% EtOAc/heptane; 2nd column silica, eluent: 0-5% MeOH/DCM) to give 35 mg (15%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 1.27 (s, 9H), 2.88 (dd, 1H), 2.98 (dd, 1H), 4.33 (quintet, 1H), 6.29 (d, 1H), 6.33 (s, 1H), 7.00 (d, 1H), 7.60 (m, 2H), 7.83 (d, 1H), 7.89 (d, 1H), 12.84 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:4]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:25]/[C:24]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[O:26])=[C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:4]=1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OCc2ccccn2)c(C=O)cc1-c1cccs1
Product: COc1cc(OCc2ccccn2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 90 %

Procedure:
The title compound was prepared by condensing 4-methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-114A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 90% yield, mp 188–189° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.66 (d, 1H, J=3.6 Hz), 8.28 (s, 1H), 8.21 (d, 2H, J=7.8 Hz), 8.11 (d, 1H, J=15.4 Hz), 7.89–7.99 (m, 4H), 7.57–7.68 (m, 4H), 7.53 (dd, 1H, J=5.4, 1.5 Hz), 7.41–7.45 (m, 1H), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 7.02 (s, 1H), 5.45 (s, 2H), 3.99 (s, 3H). MS (ESI) m/z=507 ([M+H]+, 100%). Anal. Calcd. for C26H22N2O5S2.½H2O: C, 60.57; H, 4.50; N, 5.43; S, 12.44. Found: C, 60.92; H, 4.54; N, 5.48; S, 12.32.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=1>CCCCC.C([Li])(C)(C)C.O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=1
Reactant: Brc1ccccn1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Brc1cc(-c2ccccn2)cc(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
In a stream of argon, 89 mL of a 1.57M tert-butyllithium pentane solution was dissolved in 32 mL of tetrahydrofuran, and the solution was cooled to −78° C. 10.0 g of 2-bromopyridine was added dropwise to the solution, and the mixture was stirred for 1.5 hours. 42.5 g of dichloro(tetramethylethylenediamine)zinc was added to the mixture, and the temperature of the resultant mixture was elevated to room temperature, and the mixture was further stirred for 1 hour. To the resultant mixture, a suspension of 10.0 g of 1,3,5-tribromobenzene and 734 mg of tetrakis(triphenylphosphine)palladium in 64 mL of tetrahydrofuran was added. The obtained mixture was heated under reflux for 17 hours while being stirred. Then the obtained reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Water and chloroform were added to the concentrate, and the organic phase was separated and distilled to remove the solvent. The thus-obtained crude product was purified by silica gel chromatography using an ethyl acetate/hexane (2:8-1:1) mixed solvent to give 6.5 g of the target 3,5-di(2-pyridyl)bromobenzene as a yellow solid (yield: 66%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][CH:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:47])([CH3:46])[CH3:48])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(OC2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
4-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-O-D-glucopyranosyloxy)-1H-pyrazole (5 g) was dissolved in tetrahydrofuran (18 mL). To the solution was added 10% palladium-carbon powder (500 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (4.45 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:50])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[CH:18][C:17]=1[CH2:39][O:40][C:41](=[O:49])[NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(C)(C)C>C(Cl)Cl>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:50])=[O:12])=[C:17]([CH2:39][O:40][C:41](=[O:49])[NH:42][CH:43]3[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]3)[CH:18]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Trifluoroacetic acid (0.032 mL, 0.42 mmol) was added to a solution of 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-cyclohexylcarbamoyloxymethyl-phenyl}-propionic acid tert-butyl ester (50 mg, 0.085 mmol) in CH2Cl2 (5 mL) at room temperature. The reaction mixture was stirred overnight and concentrated under vacuum to give the title compound (41 mg, 90%). 1H-NMR (200 MHz, CDCl3): δ 9.4 (br s, 1H), 7.58-7.49 (m, 4H), 7.42 (m, 2H), 7.32 (m, 1H), 7.13 (d, 1H, J=8.3), 7.00-6.93 (m, 3H), 6.84 (dd, 1H, J=7.8, 2.7), 5.11 (s, 2H), 4.76 (br s, 1H), 4.17 (m, 4H), 3.57-3.35 (m, 1H), 2.95 (t, 2H, J=7.8), 2.63 (t, 2H, J=7.8), 2.27 (qn, 2H, J=6.0), 1.99-1.05 (m, 10H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1.[C:21]([NH:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([CH3:20])=[CH:4][N:3]=[C:2]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([CH2:29][NH:28][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:31][CH:32]=2)[N:7]=1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 100 °C

Procedure:
A suspension of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6) (0.150 g, 0.518 mmol), 4-(N-Boc-aminomethyl)aniline (0.145 g, 0.621 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), Cs2CO3 (0.506 g, 1.55 mmol) and Xantphos (12 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was heated under microwave irradiation at 100° C. for 1.5 hours. The resulting mixture was filtered through a plug of silica gel, washing with 10% MeOH in DCM. The volatiles were removed in vacuo and the residue was adsorbed onto silica gel and the product purified using silica gel column chromatography (CombiFlash Rf, 12 g SiO2 cartridge, 0-5% MeOH in DCM) to give the title compound A114 as a white solid (0.043 g, 17%); 1H NMR (300 MHz, d4-MeOH) δ 8.07 (brs, 1H), 7.59 (brs, 2H), 7.19 (m, 6H), 4.19 (brs, 2H), 3.64 (brs, 2H), 3.11 (brs, 2H), 2.95-2.98 (m, 2H), 2.08 (brs, 3H), 1.46 (brs, 9H). LCMS-B: rt 6.636 min; m/z 476 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11]C)[C:5]([OH:7])=[O:6].Br.C(O)(=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1F
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(O)c(F)c1
Yield: 85.7 %

Procedure:
98.8 g of 3-fluoro-4-methoxy benzoic acid was mixed with 215 ml of concentrated hydrogen bromide solution and 215 ml of acetic acid and heated under reflux for 34 hours with stirring. Thereafter, the reaction mixture was cooled with water, and the precipitated crystal was filtered to obtain a blackish brown crystal. This crystal was recrystallized with water to obtain 77.73 g (yield: 86%) of a black crystal. Moreover, the use of this crystal itself caused no problem at the subsequent step though it may be changed into white by further purification.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:12](Br)[CH3:13].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:15]([CH:12]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:13])=[N+:16]=[N-:17]
Reactant: CC(Br)c1nc2sccn2c(=O)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
A mixture of 6-bromo-7-(1-bromoethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (3.7 g, 11 mmol) and sodium azide (1.4 g, 22 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 1.5 hour. After diluted with ethyl acetate, the mixture was washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-60% ethyl acetate/hexanes) to give the desired product (2.16 g). LCMS calculated for C8H7BrN5OS (M+H)+: m/z=300.0. Found: 300.0.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[N:7]1([CH2:12][CH2:13][O:14][C:15]2[CH:44]=[CH:43][C:18]([CH2:19][C:20]3[C:21]4[CH:42]=[CH:41][CH:40]=[CH:39][C:22]=4[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C@@H:33]4[CH2:37][CH2:36][C:35](=[O:38])[NH:34]4)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.B(Br)(Br)Br>C(Cl)Cl>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:2][O:3][C:16]1[CH:17]=[C:18]([CH:43]=[CH:44][C:15]=1[O:14][CH2:13][CH2:12][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:19][C:20]1[C:21]2[CH:42]=[CH:41][CH:40]=[CH:39][C:22]=2[S:23][C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C@H:33]2[CH2:37][CH2:36][C:35](=[O:38])[NH:34]2)=[CH:29][CH:30]=1
Reactant: O=C1CC[C@@H](COc2ccc(-c3sc4ccccc4c3Cc3ccc(OCCN4CCCC4)cc3)cc2)N1
Agent: BrB(Br)Br
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: COc1cc(Cc2c(-c3ccc(OC[C@H]4CCC(=O)N4)cc3)sc3ccccc23)ccc1OCCN1CCCC1
Reaction time: 2.5 h

Procedure:
A 0° C. slurry of 12.0 g (49.9 mmol) of 2-(4-methoxy-phenyl)benzo[b]thiophene (Example 3; Part C, above) in 250 mL of CH2Cl2 was treated with 25 g (99.8 mmol) of BBr3 in a dropwise manner. The reaction was stirred for 2.5 h and was quenched by the careful addition of 30 mL of MeOH. The mixture was concentrated in vacuo and the residue recrytallized from MeOH to afford 7.94 g (35.1 mmol; 70%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[H-].[Na+]>CN(C)C=O.Cl.O>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=2)(=[O:20])=[O:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 4,6-dichloropyrimidine (1.33 g) and 4-tert-butylbenzenesulfonamide (1.96 g) in dimethylformamide (20 ml) is added sodium hydride (60% dispersion-type, 714 mg). The mixture is stirred at room temperature for two hours, and the reaction solution is diluted with 10% hydrochloric acid and water. The mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate to give 4-tert-butyl-N-(6-chloropyrimidin-4-yl)benzenesulfonamide (2.02 g).