Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:11]3[CH:12]=[C:13]([O:16][C@@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C@@H:20]([NH2:27])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: N[C@H]1CC[C@H](Oc2ccc3nnc(N4CCCCC4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cc1
Yield: 20 %

Procedure:
A mixture of Intermediate 55a (120 mg, 0.33 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 147 mg, 0.36 mmol), DIPEA (86.0 μL, 0.50 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give a pale yellow foam. This was lyophilised to provide the title compound as an off-white solid (28 mg, 20%). LCMS (Method 5) Rt 4.76 min, m/z 619 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.61 (2H, m), 1.72 (5H, m), 2.02-2.17 (3H, m), 2.35 (3H, s), 3.13 (4H, m), 4.90 (1H, m), 5.58 (1H, m), 6.31 (1H, s), 6.99 (1H, d, J 7.8), 7.19 (1H, dd, J 9.7, 2.2), 7.26-7.43 (8H, m), 7.58-7.64 (2H, m), 7.98 (1H, s).
Reaction SMILES: [P:1]([O:16]C1C=CC=CC=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.[C:25]1(O)C=CC=CC=1.C1(OC)C=CC=CC=1>CI>[CH3:25][P:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: COc1ccccc1
Solvent: CO
Solvent: CI
Product: CP(=O)(Oc1ccccc1)Oc1ccccc1
Yield: 92 %

Procedure:
A reactor fitted with an efficient condenser, thermometer, mechanical stirrer and side-arm addition funnel was charged with 1552 g (5.0 mol) of triphenyl phosphite. The reactant was placed under a nitrogen blanket and heated to reflux. A solution of 5.0 g of methyl iodide in 160 g (5.1 mol) of methanol was then slowly added over a two hour period. Throughout the addition, the temperature of the reactor contents was maintained within the 200°-250° C. range. One further hour at 215° C. proved sufficient for the reaction to reach completion. Subsequently, an aspirator vacuum distillation removed 468 g (5.0 mol) of phenol containing a small amount of anisole. Thereafter, a high vacuum distillation recovered 1150 g (4.6 mol, 92% yield) of diphenyl methylphosphonate. Glc analysis using a 6 foot column packed with 10% OV-101 on chromosorb W, was employed to monitor the progress of both the reaction and distillation. The 31P signal for the product appeared at -24.0 ppm. Proton nmr signals were seen at τ8.36 (3 H, doublet, J=18 HZ, CH3P) and τ2.9-2.5 (10 H, multiplet, phenyl).
Reaction SMILES: C([O:4][C@H:5]1[C:14]2[N:13]=[C:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11]3[C@@H:21]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=4)[O:22][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[C:10]=3[C:9]=2[C@@H:8]([O:38][Si](C(C)(C)C)(C)C)[CH2:7][C:6]1([CH3:47])[CH3:46])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C@@H:21]2[C:11]3[C:12]([CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[N:13][C:14]4[C@H:5]([OH:4])[C:6]([CH3:47])([CH3:46])[CH2:7][C@H:8]([OH:38])[C:9]=4[C:10]=3[C:23]3([CH2:24][CH2:25][CH2:26][CH2:27]3)[O:22]2)=[CH:29][CH:30]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(=O)O[C@H]1c2nc(C3CCOCC3)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)CC1(C)C)C1(CCCC1)O[C@@H]3c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)c1ccc([C@H]2OC3(CCCC3)c3c2c(C2CCOCC2)nc2c3[C@@H](O)CC(C)(C)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
17 mg (3′R,6′R,9′S)-9′-(tert-butyldimethylsilyloxy)-3′-(4-tert-butylphenyl)-7′,7′-dimethyl-4′-(tetrahydro-2H-pyran-4-yl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]-6′-yl acetate are dissolved in 1 ml methanol and treated with 200 mg potassium carbonate. The mixture is stirred for 36 hours at room temperature, diluted with diethylether and washed with water and saturated aqueous sodium bicarbonate. The organic phase is dried with magnesium sulphate and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 80:20 to 40:60).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]O)#[N:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:31]([C:33]1[CH:34]=[C:35]([CH2:36][O:13][C:14]2[CH:15]=[C:16]([O:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:38]=[CH:39][CH:40]=1)#[N:32]
Reactant: N#Cc1cccc(CO)c1
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Diethyl azodicarboxylate (174 mg, 1.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in the preceding step, 3-cyanobenzyl alcohol (133 mg, 1.0 mmol)(Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofuran (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated NaHCO3 (2×30 mL), brine (2×30 mL) and dried over Na2SO4. The solvent was removed in vacuo the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (375 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 5.02 (s, 2H), 6.78 (m, 2H), 6.85 (dd, 1H, J=4.2, 1.3 Hz), 7.20 (t, 1H, J=8.2 Hz), 7.38 (t, 1H, J=5.8 Hz), 7.51 (t, 1H, J=7.7 Hz), 7.59-7.68 (m, 5H) and 7.93 (dd, 1H, J=4.0, 0.7 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[N:17]=[C:18]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[S:19][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[S:19][C:18]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[N:17][C:16]=1[CH3:15])=[O:22]
Reactant: Cc1nc(-c2cnccn2)sc1C(=O)Cl
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cnccn2)sc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 56.5 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0486 g, 0.190 mmol), 4-methyl-2-(pyrazin-2-yl)thiazole-5-carbonyl chloride (0.047 g; 0.190 mmol), and triethylamine (0.067 mL; 0.475 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 3 to 30% of ethyl acetate in dichloromethane gave 0.0427 g (56%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-methyl-2-(pyrazin-2-yl)thiazole-5-carboxamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14])[C:6](Cl)=NC.[N:18]1[NH:19]N=[N:21][C:22]=1[C:23]1[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=[CH:27][CH:28]=1.N1C=CC=C[CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:21]([CH3:34])[C:22]([C:23]3[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:18][N:19]=2)[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14]
Reactant: CN=C(Cl)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Reactant: FC(F)(F)c1ncccc1-c1nn[nH]n1
Reactant: c1ccncc1
Product: COc1cc(-c2nnc(-c3cccnc3C(F)(F)F)n2C)cc([N+](=O)[O-])c1OC
Temperature: 82.5 °C

Procedure:
3,4-Dimethoxy-N-methyl-5-nitro-benzimidoyl chloride (0.28 g, 1.08 mmol) was added to a stirred solution of 3-(2H-tetrazol-5-yl)-2-(trifluoromethyl)pyridine (0.215 g, 1 mmol) in dry pyridine (3 mL), preheated to 50° C. The resulting mixture was cautiously heated to 75-90° C. and maintained at this temperature until nitrogen evolution ceased. The mixture was then poured onto water (30 mL) and extracted with dichloromethane (25 mL). The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resulting residue was purified by chromatography to afford 3-(5-(3,4-dimethoxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(trifluoromethyl)pyridine, 0.241 g (59%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]([O:15][CH3:16])[CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1ccc(Cl)nc1

Procedure:
A solution of (6-chloropyridin-3-yl)acetic acid (5.0 g), N,O-dimethylhydroxyamine hydrochloride (2.98 g), EDC.HCl (5.87 g), and N-methylmorpholine (9.6 mL) in DMF (70 mL) was stirred at room temperature for 4 days. Under ice cooling, water (150 mL) was added thereto, followed by extraction with EtOAc. The organic layer was sequentially washed with water and brine and was dried over Na2SO4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil: 50 g, mobile phase: n-hexane/EtOAc=75/25 to 0/100 (v/v)) to yield the title compound (3.56 g, light yellow oil).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[Na+].O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(Br)ccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (3.96 g, 15 mmol) dissolved in DMF (16 mL) were added sodium cyanide (0.85 g, 17.25 mmol) and water (1.8 mL). The reaction was stirred for overnight at room temperature. To the reaction was added 100 mL water; 80 mL saturated NaHCO3, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3×100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (2.92 g, 92.7% yield). 1H NMR (400 MHz, CDCl3): δ 2.32 (2 H, s), 3.62 (1 H, s), 7.20–7.27 (1 H, m), 7.32–7.41 (1 H, m).
Reaction SMILES: [OH2:1].[C:2]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[CH:3]1.[C:9]([OH:13])(=[O:12])[CH2:10][SH:11]>>[C:9]([CH2:10][S:11][CH:3]([CH2:4][C:5]([OH:1])=[O:6])[C:2]([OH:7])=[O:8])([OH:13])=[O:12]
Reactant: O
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)CS
Product: O=C(O)CSC(CC(=O)O)C(=O)O
Temperature: 90 °C

Procedure:
A solution of 180 g (10 mol) of water and 98 g (1.0 mol) of maleic anhydride was heated to 40° C. To this solution was added 92 g (1.0 mol) of thioglycolic acid and the reaction mixture was heated to 90° C. with stirring. After three (3) hours at 90° C., the water was evaporated off under reduced pressure. The resulting molten product was cast and ground prior to use.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH:8]=[O:9])[S:5][CH:4]=1)#[N:2].O1C[CH2:13][CH2:12][CH2:11]1.C([Mg]Cl)(C)C.C(OCC)(=O)C>CCOCC>[C:1]([C:3]1[CH:7]=[C:6]([CH:8]([OH:9])[CH:12]([CH3:13])[CH3:11])[S:5][CH:4]=1)#[N:2]
Reactant: C1CCOC1
Reactant: N#Cc1csc(C=O)c1
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)C(O)c1cc(C#N)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
3-Cyano-5-thiophenecarboaldehyde (2.00 g) was dissolved in anhydrous ether (100 ml) and anhydrous tetrahydrofuran (THF) (20 ml), and an ether solution (10.9 ml) of (2.0 M) isopropylmagnesium chloride was added thereto. After stirring at 0° C. for 2 hours, ethyl acetate was added thereto. The mixture was washed with an aqueous saturated ammonium chloride and further brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a pale yellow oil (1.25 g, 47%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[O:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ncoc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ncoc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 84.7 %

Procedure:
In the same manner as in Example 259 and using 4-methyl-1,3-oxazole-5-carboxylic acid (76 mg, 0.59 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.71 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting material, the title compound (170 mg, 84%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[C:17]([CH3:20])([CH3:19])[CH3:18].[C:21]1([CH2:27][CH2:28]O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:21]1([CH2:27][CH2:28][O:15][C:14](=[O:16])[CH2:13][CH2:12][C:5]2[CH:4]=[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:2]([OH:1])=[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: OCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)OCCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid-2-phenylethyl ester was prepared from 278 g (1 mol) of 3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid and 122 g (1 mol) of 2-phenylethanol by azeotropic esterification in toluene with 0.5 g of 4-toluenesulfonic acid. The product was analyzed and the results of this analysis were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[IH:19]>>[I:19][C:12]1[CH:17]=[C:16]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:15]=[CH:14][N:13]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Clc1ccccc1-c1cc(I)ncn1

Procedure:
The compound was prepared according to Example 1 using 2-chlorophenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O.C(OO[C:31](=[O:38])C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:38][CH3:31])=[CH:6][C:5]=1[CH2:11][Br:13]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(F)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1CBr
Temperature: 25 °C

Procedure:
4-Fluoro-2-methyl-benzoic acid methyl ester (600 mg, 3.6 mmol), N-bromosuccinimide (635 mg, 3.6 mmol) and benzoyl peroxide (43 mg, 1.79 mmol) in CCl4 (15 mL) was stirred at 90° C. for 3 hours. The reaction was cooled to room temperature, filtered, washed with CCl4 and the solvent was removed under reduced pressure to provide a white solid. 1H NMR (300 MHz, CDCl3): δ 8.01 (d, 1H), 6.99 (d, 1H), 6.88 (dd, 1H), 4.98 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH:24](O)[CH3:25])=[CH:16][CH:15]=1)[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH2:24][CH2:25][O:2][CH:1]=[O:3])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc2c(=O)c(C(=O)O)cn(C(C)O)c2n1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Reaction time: 0.75 h

Procedure:
Formic acid (1 ml) was added to acetic anhydride (2 ml) which was cooled to 0°. The mixture was warmed to 50° for 15 minutes, cooled to 0° and added to a suspension of 7-ethoxy-1,4-dihydro-1-hydroxyethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.78 g) in dry pyridine (10 ml). The mixture was stirred at 0° for 45 minutes and then for 1 hour at room temperature. The solid was collected and washed with water and dried, m.p. 208.5°-210° (d). (71 %).
Reaction SMILES: O[CH:2](O)[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[CH3:17][C:18]([CH3:28])([NH2:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C.CN(C)C=O>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:2][NH:27][C:18]([CH3:28])([CH3:17])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCc2cc(C(=O)C(O)O)ccc2N1
Reactant: CC(C)(N)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(CCc1ccccc1)NCC(O)c1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.4 g (0.006 mole) of 3,4-dihydro-6-(alpha,alpha-dihydroxy-acetyl)-quinolin-2-(1H)-one and 1.37 g (0.008 mole) of 1,1-dimethyl-3-phenyl-propanamine in 60 ml of ethanol and 30 ml of dimethylformamide is heated to 80° C. for 2 hours and, after cooling to room temperature, about 1.5 g of sodium borohydride are gradually added. After 2 hours, the mixture is acidified with acetic acid and the solvent is evaporated off in vacuo. After being rendered alkaline with 2N sodium hydroxide solution, the residue is extracted with methylene chloride. The residue of the organic phase is purified by column chromatography on silica gel (CHCl3 /MeOH 93/7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C([N:30](C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([NH2:30])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Yield: 111 %

Procedure:
A solution of [piperidin-4-ylmethyl]-carbamic acid t-butyl ester (4.28 g, 20 mmol), 4-fluorobenzenesulfonyl chloride (3.89 g, 20 mmol), and diisopropylethyl amine (3.5 mL, 20 mmol) in 50 mL of CH2Cl2 was stirred at ambient temperature overnight. The reaction mixture was diluted to twice its volume with CH2Cl2 and washed with 1N HCl, brine and dried (Na2SO4). The solvent was evaporated in vacuo to give 8.2 g of product as a white solid.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])=[O:12])[N:8]=1)([CH3:3])[CH3:2].[NH2:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]1[S:48][CH:47]=[N:46][CH:45]=1)=[O:41])[CH2:33][C:34]1[S:38][CH:37]=[N:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([NH:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]2[S:48][CH:47]=[N:46][CH:45]=2)=[O:41])[CH2:33][C:34]2[S:38][CH:37]=[N:36][CH:35]=2)[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])[CH:15]([CH3:16])[CH3:17])=[O:12])[N:8]=1)([CH3:2])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cncs1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(COC(=O)N[C@H](C(=O)O)C(C)C)cs1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1nc(COC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](Cc2cncs2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane provided, after silica gel chromatography using 1% methanol in chloroform, 54 mg (66%) of the desired compound (Rf 0.6, 10% methanol in CH2Cl2). 1H NMR (DMSO-d6) δ 0.69 (d, 3 H), 0.74 (d, 3 H), 1.31 (d, 6 H), 1.47 (m, 2 H), 1.85 (m, 1 H), 2.75 (m, 4 H), 2.95 (m, 1 H), 3.57 (m, 1 H), 3.80 (m, 2 H), 4.08 (m, 1 H), 4.95 (d, 1 H), 5.03 (s, 2 H), 5.19 (s, 2 H), 7.12-7.29 (m), 7.45 (s, 1 H), 7.47 (s, 1 H). Mass spectrum: (M+H) +=715.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23]CC)=[O:22])=[CH:8]1>S(=O)(=O)(O)O.C(O)(=O)C.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
A mixture of 6.0 g of ethyl(2,3,4,5-tetrafluorobenzoyl)acetate, 5.8 g of ethyl orthoformate and 6.3 g of acetic anhydride was refluxed for 2 hours. After distillation under reduced pressure, the residue was dissolved in 50 ml of ethanol. To this solution, 2.8 g of 2-aminomethylthiazole was added, followed by stirring for 2 hours, while ice cooling. The reaction product was added to 100 ml of ice water, and the resulting crystal was collected by filtration and dried. The 8.0 g crystal obtained was dissolved in 50 ml of dimethylformamide, and 2.0 g of 60% oily sodium hydride was added, followed by heating and stirring at 100° to 110° C. for 2 hours. The reaction product was added to 100 ml of ice water and extracted with dichloromethane (100 ml×3). The extract was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure, to yield 5.4 g of ethyl 1-(thiazol-2-yl)methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate. Next, 5.0 g of this ester was dissolved in a mixture of 3 ml of sulfuric acid, 20 ml of acetic acid and 18 ml of water, followed by stirring at 110° to 120° C. for 1.5 hours. The reaction product was added to 100 ml of ice water to cause crystallization. The resulting crystal was collected by filtration, washed with water and dried to yield 4.4 g of the title compound.