Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]#[C:17][CH2:18][OH:19])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[NH2:21][N+:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1.O>CC#N>[CH2:1]([O:8][C:9]1[C:10]([C:16]2[C:17]([CH2:18][OH:19])=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[n+]1ccccc1
Reactant: OCC#Cc1nc(Cl)ccc1OCc1ccccc1
Agent: [I-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: OCc1c(-c2nc(Cl)ccc2OCc2ccccc2)nn2ccccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
A mixture of compound 3-(3-(benzyloxy)-6-chloropyridin-2-yl)prop-2-yn-1-ol (1.9 g, 6.9 mmol), 1-aminopyridinium iodide (2.3 g, 10.4 mmol) and DBU (2.2 g, 14 mmol) in MeCN (15 mL) was stirred at 80° C. for 2 hours. Water (15 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (petroleum ether:ethyl acetate=1:1) to provide the product of compound (2-(3-(benzyloxy)-6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanol (1.2 g, yield: 47%). 1H-NMR (CDCl3, 400 MHz) δ 8.42 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.29˜7.22 (m, 3H), 7.21˜7.17 (m, 3H), 7.02 (t, J=8.0 Hz, 1H), 6.76 (dt, J=1.6, 8.0 Hz, 1H), 5.09 (s, 2H), 4.77 (d, J=6.4 Hz, 2H). MS (M+H)+: 366/368.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][O:40][CH2:41][CH2:42][NH2:43]>C(N(CC)CC)C>[CH3:39][O:40][CH2:41][CH2:42][NH:43][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:32])[F:33])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:12][CH:13]=1
Reactant: COCCN
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Solvent: CCN(CC)CC
Product: COCCNCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-methoxyethanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=61-62° C. 1H NMR 400 MHz (DMSO-d6) δ 9.55 (s, 1 H); 8.38-8.34 (m, 2 H), 7.82-7.75 (m, 3 H), 7.56 (t, 1 H), 7.49-7.40 (m, 3 H), 7.27 (d, J=7.6 Hz, 1 H), 7.17-7.15 (m, 2 H), 6.76 (d, J=7.2 Hz, 1 H), 4.64 (t, J=7.2 Hz, 1 H), 3.39-3.35 (m, 3 H), 3.23 (s, 3 H), 3.21-3.11 (m, 2 H), 2.76-2.64 (m, 6 H). LCMS 519 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of ethyl 4-hydroxybenzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-Allyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.56 (s, —CO2H); 7.83 (d-like, J=8.0, 2 arom. H); 6.97 (d-like, J=8.0, 2 arom. H); 5.99 (m, —CH═CH2); 5.38, 5.24 (2 d-like, —CH═CH2); 4.59 (d-like, CH2—CH═CH2); 13C-NMR (100 MHz, d6-DMSO): 166.92 (—C═O); 161.72; 133.17; 131.28 (2 arom. C); 123.04; 117.80; 114.42 (2 arom. C); 68.34.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](O)=[CH:17][CH:18]=1)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:17][CH:18]=1
Reactant: OCc1ccccn1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 146.5 %

Procedure:
To a solution of THF (50 mL) of 2-(hydroxymethyl)pyridine (1.5 g), methyl p-hydroxybenzoate (2.1 g), and triphenylphosphine (5.0 g) was added diisopropyl azodicarboxylate (3.9 g) at 0° C., which was stirred for 20 minutes at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by NH silica gel chromatography (heptane:ethyl acetate=2:1), then purified by silica gel chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (4.9 g).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][CH2:70][N:71]1[CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:67][CH2:68][CH2:69][CH2:70][N:71]3[CH2:75][CH2:74][CH2:73][CH2:72]3)=[O:17])[CH:12]=2)[CH:6]=1
Reactant: NCCCN1CCCC1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
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
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC5)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (150 mg, 0.33 mmol) in 10 ml of anhydrous DMF were added HATU (152 mg, 0.40 mmol) and N,N-diisopropylethylamine (94 mg, 0.73 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)pyrrolidine (85 mg, 0.66 mmol), and stirring was continued for another 10 minutes. The mixture was poured into 50 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 160 mg, 86%.
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[S:13][CH:14]=1.CCCCCC>C(OCC)(=O)C>[ClH:1].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[S:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (4.20 g, 11.0 mmol) in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 14 hours. Hexane was added to the reaction mixture, and crystals were collected by filtration to give 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine hydrochloride. The hydrochloride was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.76 g (56.8%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:34]4[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[C:36]([O:37][CH3:38])[CH:35]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Product: COc1ccc(-c2ccc3c(c2)CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1OC
Reaction time: 0.33 h
Yield: 52 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,4-dimethoxyphenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCCOCCCl
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(Br)cc1C
Temperature: 90 °C
Reaction time: 168 h

Procedure:
To a solution of 4-bromo-2-methylphenol (10.46 g) in DMF (10 ml) were added at room temperature potassium carbonate (11.5 g), sodium iodide (9.97 g) and 2-chloroethylpropylether (5.6 ml), and the mixture was stirred at 90° C. for 7 days. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N sodium hydroxide solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:9) to give pale yellow oil of 4-bromo-2-methyl-1-(2-propoxyethoxy)benzene (11.7 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25]([O:28][C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35](O)=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([O:28][C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(OC(C)=O)cc1
Yield: 94 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-acetoxycinnamic acid (2.9 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.5 g, 93%) as an oily product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].[Li]CCCC.[C:45](OC(=O)C)(=[O:47])[CH3:46].[Cl-].[NH4+]>C1COCC1.CCOCC.O>[O:47]=[C:45]([CH3:46])[CH2:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 25 °C

Procedure:
2.7 g trans-2-(3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (STEP I) dissolved in 15 mL THF was cooled to -78° and treated with 5.3 mL of 1.6M n-BuLi. After about 5 minutes of stirring, to the resulting dark solution, 1.0 mL of acetic anhydride was added. The yellow reaction mixture was allowed to warm up to room temperature and treated with 3-4 g of solid ammonium chloride, water and ether. NMR showed that the desired ketosulfone has formed to the extent of 80%. The ether layer was separated, dried over NaSO4, evaporated and chromatographed over silica (20% ethyl acetate in hexane) to yield the title compound after crystallization from ether: NMR(200 MHz, CDCl3) δ 0.98(t, CH2CH2CH3), 1.83(m, CH2CH2CH3), 1.9-2.6(m, 3-CH2 and 4-CH2), 2.38(s, CH3C(O)CH2), 3.86(s, OCH3), 3.88(s, 2 OCH3), 4.18(t, OCH2CH2CH3), 4.48(s, CH3C(O)CH2), 5.18(s, OCH2Ar), 5.06-5.28(m, 2-CH and 5-CH), 6.61(s, 5-ArH), 7.32-7.54(m, ArH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 65 %

Procedure:
A mixture of 180 mg (0.36mmol) of (2S,3R, 4R, 5S)-2,5-di-(N-((t-butyloxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane and 180 mg of 5% rhodium on carbon in 50 ml of methanol was shaken under 4 atmospheres of hydrogen for 24 h. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 5% ethyl acetate in hexane to provide 120 mg (65%) of the desired compound (Rf 0.35, 30% ethyl acetate in hexane) as a white solid, m.p. 224°-226° C. Mass spectrum: (M+H)+ =513.
Reaction SMILES: [K].[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([CH3:29])[C:11]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)=[S:17])(=[O:14])=[O:13])=[O:6])[CH3:3].BrBr>N1C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([O:27][CH3:28])[N:20]2[S:17][C:16](=[N:15][S:12]([C:11]3[N:10]([CH3:29])[N:9]=[CH:8][C:7]=3[C:5]([O:4][CH2:2][CH3:3])=[O:6])(=[O:13])=[O:14])[N:18]=[C:19]2[N:24]=1
Reactant: CCOC(=O)c1cnn(C)c1S(=O)(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Agent: BrBr
Agent: [K]
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(C)c1S(=O)(=O)N=c1nc2nc(OC)cc(OC)n2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0 g of potassium salt of N-(4-ethoxycarbonyl-1-methyl-5-pyrazolesulfonyl)-N'-(4,6-dimethoxy-2-pyrimidinyl)thiourea (acetonitrile-solvate product) is dissolved in 20 ml of pyridine, and to the solution is added dropwise 0.37 g of bromine while cooling at -6° C. to -8° C. The reaction mixture is stirred at the same temperature for 2 hours, and poured into 100 ml of ice water. The resulting crystals are filtered, washed with water, and recrystallized from acetonitrile to give 0.5 g of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].CCN(C(C)C)C(C)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>ClCCl>[CH:1]1([CH2:6][C@@H:7]([C:8](=[O:9])[N:10]2[C@H:14]([C:15]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O
Reactant: Nc1ccccn1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1000 ml round bottom flask under N2 was added (5S)-1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (27.7 g, 79 mmol) in dichloromethane (DCM) (700 mL) at 0° C., followed by 2-pyridinamine (14.79 g, 157 mmol), DIPEA (68.6 mL, 393 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (21.40 g, 157 mmol) and EDC (30.1 g, 157 mmol). The mixture was allowed to warm up to room temperature and stirring continued overnight. LCMS showed that the desired product was ˜56%. After another 24 h, LCMS indicated no starting material left. The organic solution was washed with water (300 mL), 10% citric acid (2×300 mL) and brine, dried (Na2SO4), filtered, and concentrated to afford 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{(5S)-5-[(2-pyridinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (29.1 g, 58.4 mmol, 74% yield) as a brown gummy solid. LCMS: [M+H]+: 429.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5](O)[CH2:4][CH2:3]1>C(O)(=O)C(O)=O.O>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH2:3]1
Reactant: CC1(C)CCC(O)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: O
Product: CC1(C)CC=Cc2ccccc21

Procedure:
A mixture of 1,2,3,4-tetrahydro-4,4-dimethyl-1-naphthol (9.6 g, 54.5 mmoles) in 20% aqueous oxalic acid was stirred and heated to reflux for 5 hours. After cooling, the reaction mixture was diluted with one volume of water and then extracted with one volume of ether. The aqueous layer was extracted again with one volume of ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered, and evaporated under reduced pressure to leave an oil which was purified using silica gel column chromatography, eluting with ethyl acetate:hexane (0.1:49.9) to give 1,2-dihydro-1,1-dimethylnaphthalene as a colorless oil. (4.76 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:37])[CH2:9][CH2:10][C@@H:11]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)[N:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:12]2=[O:36])=[CH:4][CH:3]=1.[C:38]([O:41][C@@H:42]1[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:46]([O:52][C:53](=[O:55])[CH3:54])[C@@H:45]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[O:44][C@H:43]1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63](Br)[CH:62]=1)(=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:38]([O:41][C@@H:42]1[C@@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:46]([O:52][C:53](=[O:55])[CH3:54])[C@@H:45]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[O:44][C@H:43]1[C:61]1[CH:62]=[C:63]([C:18]2[CH:17]=[CH:16][C:15]([C@@H:14]3[C@@H:11]([CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[OH:37])[C:12](=[O:36])[N:13]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:20][CH:19]=2)[CH:64]=[CH:65][CH:66]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Br)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC1(C)OB(c2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccccc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 18.4 %

Procedure:
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidin-2-one (51.3 mg, 0.102 mmol) and (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol (35.5 mg, 0.073 mmol) were dissolved in 2.0 mL of toluene and 0.25 mL of ethanol. 0.075 mL of 4 N potassium carbonate was added to the mixture followed by 5.0 mg of tetrakis(triphenylphosphine)palladium(0). The entire reaction was degassed three times with argon then heated to reflux for 4 h. The reaction was cooled to room temperature, diluted with 5 mL of water, and extracted with ethyl acetate (3×25 mL). The organic layers were combine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford 10.5 mg (13%) of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29]([O:31]C)=[O:30].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29]([OH:31])=[O:30]
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(OC)cn3)CC2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1

Procedure:
Methyl [2-fluoro-4-(2-{(1S,2R)-2-[1-(5-methoxypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)phenyl]acetate (1.41 g, 3.28 mmol) was dissolved in MeOH (15 ml) and sodium hydroxide (5 M, 3.18 ml, 15.9 mmol) was added. The mixture was stirred at RT for 1 h and neutralized to pH 5 with 5 M HCl (5 ml), extracted with EtOAc (50 ml). The organic phase was dried over MgSO4, and evaporated to afford the title compound. LC/MS (m/z): 430 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:4][CH2:5][CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[I-:28].[Na+].C(OCC)(=O)C.O>CC(C)=O>[CH2:1]([N:3]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:4][CH2:5][CH2:6][I:28])[CH3:2]
Reactant: [I-]
Reactant: CCN(CCCOS(=O)(=O)c1ccc(C)cc1)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CCCI)C(=O)OCc1ccccc1
Yield: 76.3 %

Procedure:
N-Ethyl 3-benzyloxycarbonylamino-1-tosyloxypropane (1.02 g) was dissolved in acetone (20 ml), and to the resulting solution was added sodium iodide (0.80 g). The resultant mixture was stirred at 45° C. for 2 hours. Ethyl acetate and water were added to the reaction solution obtained, and the organic layer so separated was washed with water and then dried over magnesiumsulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus to afford the titled compound (0.69 g; 76%).