Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][CH:52]([OH:64])[CH2:53][N:54]1[CH2:63][CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55]1>CN(C=O)C.O>[CH2:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:62][CH2:63][N:54]1[CH2:53][CH:52]([OH:64])[CH2:51][NH:50][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][CH:15]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccc(OC2CCOCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccc(OC2CCOCC2)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To a solution of 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (150 mg, 0.67 mmol) in DMF (4 mL) was added DIEA (260 mg, 2.01 mmol), HATU (384 mg, 1.01 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (170 mg, 0.81 mmol). The reaction mixture was stirred at 22° C. for 16 h. The mixture was treated with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was was purified by prep-HPLC to give the title compound (206.1 mg, Yield 74.9%). 1H NMR (CD3OD, 400 MHz): δ 7.84 (d, J=8.8 Hz, 2H), 7.26-7.37 (m, 3H), 7.19-7.25 (m, 1H), 7.05 (d, J=8.8 Hz, 2H), 4.59-4.74 (m, 2H), 4.31-4.49 (m, 2H), 3.93-4.01 (m, 2H), 3.86 (brs, 1H), 3.63 (ddd, J=11.7, 8.8, 3.0 Hz, 2H), 3.53 (qd, J=14.0, 5.7 Hz, 3H), 3.37-3.44 (m, 1H), 3.11-3.32 (m, 3H), 2.02-2.12 (m, 2H), 1.69-1.81 (m, 2H). LCMS (m/z): 411.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH:11]([N:24]1[CH2:27][C:26]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-Methoxyphenylmagnesium bromide (5.9 ml, 1M solution in tetrahydrofuran, 5.9 mmol) was added to a cooled (−78° C.) solution of 1-benzhydryl-azetidin-3-one (WO 9412181) (1 g, 4.2 mmol) in tetrahydrofuran (20 ml), and the reaction stirred at −78° C. for 15 minutes, then allowed to warm to room temperature over 30 minutes. The mixture was partitioned between water (100 ml) and ethyl acetate (100 ml), the layers separated, and the aqueus phase extracted with ethyl acetate (100 ml). The combined organic solutions were washed with brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using pentane:ethyl acetate (50:50) as eluant to afford the title compound as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2].[Br:13]Br.O>C(O)(=O)C>[Br:13][C:8]1[CH:9]=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[NH2:7]
Reactant: BrBr
Reactant: CCc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of 4-ethyl-2-nitroaniline (28 g) in acetic acid (250 ml) was added bromine (9.64 ml) dropwise with stirring at room temperature. The reaction mixture was stirred for 1 hour, poured into water, and extracted with ethyl acetate (3×200 ml). The organic layer was washed with water (3×200 ml), brine (2×100 ml), dried over magnesium sulphate and evaporated to yield 2-bromo-4-ethyl-6-nitroaniline (38 g). This was dissolved in ethanol (200 ml), concentrated sulphuric acid (24 ml) was added dropwise, the mixture heated to reflux and solid sodium nitrate (27 g) added in small amounts over 30 minutes. The reaction mixture was refluxed for a further 1 hour, cooled and poured into ice water. The product was extracted into ethyl acetate which was washed with water (2×100 ml). brine (2×100 ml), dried over magnesium sulphate and evaporated to yield 3-bromo-5-ethyl-nitrobenzene (35.5 g), δ (60 MHz, CDCl3), 1.3 (3H, t, CH3), 2.8 (2H, q, CH2) 7.6 (1H, s, 4-H), 7.9 (1H, s. 6-H) and 8.0 (1H, s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.Cl.[CH3:12][C:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O)C.C(N(CC)CC)C>CO.ClCCl.ClCCl>[CH2:22]([O:21][C:19]([C:13]1([CH3:12])[CH2:18][CH2:17][N:16]([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 80 °C
Yield: 61 %

Procedure:
To 2-chloropyrimidine-5-boronic acid (4.00 g, 25.3 mmol) were added ethyl 4-methylpiperidine-4-carboxylate hydrochloride (4.09 g, 23.9 mmol), ethanol (40 mL) and triethylamine (9.0 mL, 64.0 mmol). The mixture was heated at 80° C. for 3 h before being concentrated in vacuo. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL), then the aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with brine (100 mL), then dried (Na2SO4). The solvent was then removed under reduced pressure and the crude reaction mixture was purified by flash column chromatography on silica (Biotage SNAP 100 g, Isolera). Gradient elution, with 100% dichloromethane to 30% methanol/dichloromethane, afforded the title compound (4.27 g, 43% yield, 74% purity) as a brown oil. LCMS (pH 10): MH+ m/z 294.1, RT 0.652 minutes.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44]>>[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([I:1])=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44]
Reactant: COC(=O)c1c(Nc2ccccc2F)cncc1-c1ccccc1Cl
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
N-iodosuccinimide (236 mg, 1.05 mmol) and p-toluenesulfonic acid monohydrate (400 mg, 2.1 mmol) were added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-phenylamino)-isonicotinic acid methyl ester (300 mg, 0.84 mmol), and stirred overnight at 60° C. The reaction mixture was quenched with Na2S2O3 (1 mL, 10% aqueous solution), diluted with CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 55% EtOAc in hexanes to afford the desired product (343 mg, 85%). LC-MS (M+H=483, obsd.=483).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[O:25])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[N:11]1([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:25])[CH2:21][CH2:22]2)=[O:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)CN2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)CN2CCNCC2)CC1
Yield: 114.2 %

Procedure:
Compound 50 (110 mg, 0.21 mmol) was deprotected by stirring overnight with 10% Pd/C in ethanol (15 mL) under a hydrogen atmosphere. The reaction was filtered through a bed of celite and the filtrate evaporated to give intermediate 1-(1-((piperazin-1-yl)acetyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (103 mg, quantitative) as a clear oil, which was used without purification and coupled with acetic acid by Method E. Flash chromatography eluted with 9:1 DCM:MeOH and recrystallization from EtOAc:hexanes afforded compound 51 (73 mg, 74% over 2 steps) as a white solid: Mp 111-122° C. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 6.25 (d, J=7.7 Hz, 1H), 4.15 (d, J=13.1 Hz, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.76-3.67 (m, 1H), 3.47-3.38 (m, 4H), 3.25 (d, J=13.5 Hz, 1H), 3.12 (q, J=13.0 Hz, 2H), 2.81 (t, J=11.5 Hz, 1H), 2.37-2.32 (m, 2H), 1.98 (s, 3H), 2.44-2.40 (m, 2H), 1.90-1.77 (m, 2H), 1.42-1.31 (m, 1H), 1.26-1.15 (m, 1H). Purity 90%. HRMS calculated for C20H21F3N4O3−H+ 470.2015. found (ESI(−), [M−H]) 470.2009.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]4[CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O1CCOCC1.Cl>O>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]4[CH2:46][CH2:47]4)[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C4CC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C2CC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 1 h

Procedure:
Methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-cyclopropylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (70 mg, 0.100 mmol), lithium hydroxide monohydrate (21.02 mg, 0.501 mmol), 1,4-dioxane (1.670 mL) and water (1.670 mL) were stirred at room temperature. LCMS indicated about 8% conversion when reaction time was 1 h. LCMS trace of reaction aliquot at reaction time 18 h indicated completion of reaction. Reaction mixture was acidified by HCl (aq., 1N). Volatiles were removed under reduced pressure. The resulting pot residue was purified by a reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 100% organic in 10 min, hold 100% in 2 min). Related fractions were pooled and evaporated in vacuo to afford an aqueous mixture. The resulting aqueous mixture was extracted with EtOAc, washed with water, dried (Na2SO4), filtered and concentrated to afford a light yellow solid as the titled compound. LCMS calc.=684.21; found=685.96 (M+1)+. 1H NMR (500 MHz, CDCl3, 2:1 mixture of atropisomers): δ 8.02-7.90 (m, 3H), 7.85 (s, 1H), 7.70 (s, 2H), 7.50-7.44 (m, 1H), 7.37-7.28 (m, 1.5H), 7.16-7.09 (m, 2.5H), 5.70 (d, J=7 Hz, 0.67H), 5.63 (d, J=7.5 Hz, 0.33), 5.02 (d, J=15-5 Hz, 0.5H), 4.72 (d, J=15.5 Hz, 0.5H), 4.59 (d, J=16 Hz, 0.5H), 4.46 (d, J=16 Hz, 0.5H), 4.44-4.36 (m, 0.67H), 4.14-4.22 (m, 0.33H), 3.92-3.84 (m, 3H), 2.71 (br s, 0.67H), 2.61 (br s, 0.33H), 2.39 (s, 2H), 2.35 (s, 1H), 2.51-1.40 (m, 2H), 1.15-1.10 (m, 2H), 0.74 (d, J=6.5 Hz, 2H), 0.65 (d, J=5.5 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(=O)(=O)(O)O.C1C2C(=CC=CC=2)C=CC=1.N([O-])=O.[Na+].[I-:33].[K+].II>O.C(Cl)Cl>[I:33][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc(N)cc2ccccc12
Reactant: [I-]
Agent: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: c1ccc2ccccc2c1
Solvent: O
Solvent: ClCCl
Product: COc1cc(I)cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
50 g of 3-amino-1-methoxynaphthalene was added to 750 mL of 6 N sulfuric acid. The mixture was heated to dissolve the naphthalene and the resulting solution was cooled to 0° C. To the resulting slurry of amine hydrosulfate salt at 0° C. was added a solution of 20 g of sodium nitrite in 30 mL of water. The resulting mixture stirred at 0° C. for 1 hour and was then poured into a solution of 100 g of potassium iodide and 20 g of iodine in 400 mL water. After stirring for 1 hour at room temperature, 250 mL methylene chloride was added. The layers were separated and the aqueous portion was extracted with 3×100 mL methylene chloride. The organic portion was combined with the methylene chloride extracts and was washed with 3×75 mL saturated sodium bisulfite, dried over anhydrous magnesium sulfate, filtered, and stripped. The resulting product was pre-adsorbed onto silica and eluted with hexane. The appropriate fractions were combined, concentrated and the residual oil was further purified by HPLC to yield 15 g of 3-iodo-1-methoxynaphthalene as a yellow oil. The structure was confirmed by NMR.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C.O>[CH3:19][CH:18]([CH3:20])[CH:17]([O:16][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[O:21][C:22]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:23]
Reactant: NC1(C(=O)O)CC1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: CC(C)C(OC(=O)NC1(C(=O)O)CC1)OC(=O)c1ccccc1
Yield: 23.2 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.726 g, 7.15 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (2 g, 5.96 mmol) were reacted in the acetonitrile/water mixture to provide 0.445 g (25% yield) of the title compound (12) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=8.02 (d, 2H), 7.59 (t, 1H), 7.42 (t, 2H), 6.82 (d, 1H), 5.56 (br s. 0.3H), 5.44 (s, 0.7H), 2.21 (m, 1H), 1.61 (m, 2H), 1.39 (m, 2H), 1.02 (dd, 6H). MS (ESI) m/z 344.19 (M+Na)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M18) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (28 mg).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.I[CH:18]([CH3:22])[CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:22][O:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1
Reactant: CC(I)CCCl
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Product: CCCCCCCCC1(C)SC(=O)C=C1OCCCCCl
Yield: 76.8 %

Procedure:
From 32 (47 mg, 0.18 mmol) and 3-iodo-1-chlorobutane (40 μL, 0.36 mmol) following general procedure H was obtained 41 (46 mg, 85%) after flash chromatography (20% EtOAc/Hexanes). 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=7 Hz, 3H), 1.07-1.27 (m, 1H), 1.24 (s, 10H) 1.48-1.51 (m, 1H), 1.62 (s, 3H), 1.75-1.82 (m, 2H), 1.89-1.98 (m, 4H), 3.59 (t, J=5.9 Hz, 2H), 3.95-3.98 (m, 2H), 5.28 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 25.1, 26.0, 26.5, 29.0, 29.2, 29.3, 29.5, 29.7, 31.8, 44.1, 59.6, 71.7, 101.6, 186.1, 193.8. Analysis Calculated for C17H29C2S: C, 61.3; H, 8.78, Found: C, 61.9; H, 9.01.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:17](=[O:19])[CH:16]([N:15]1[CH2:14][C:5]2[CH2:4][C:3]3[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:6]=2[C:12]1=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: Nc1ccccn1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(C(=O)Nc1ccccn1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 220.1 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol), commercially available 2-aminopyridine (101 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, to afford S)-2-(8-Chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid pyridin-2-ylamide (970 mg, 26.4%), as a white solid. 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.34 (d, J=3.9 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.21-7.42 (m, 2H), 7.02-7.17 (m, 2H), 5.07 (d, J=4.9 Hz, 1H), 4.44 (d, J=18.6 Hz, 1H), 4.07 (d, J=18.6 Hz, 1H), 3.75 (s, 2H), 1.75-1.90 (m, 1H), 1.61-1.74 (m, 1H), 1.46 (br. s., 1H), 1.24 (s, 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41]
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(C(F)(F)F)nc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethyl)phenoxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (35 mg, 0.060 mmol) in THF (4 mL) and water (4 mL) was added LiOH.H2O (5.04 mg, 0.12 mmol). The reaction was stirred for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethyl)phenoxy)-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13 mg, 39.0% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.63 (s, 1H), 8.51 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.23 (d, J=9.2 Hz, 1H), 6.98 (s, 1H), 4.78 (s, 2H), 4.50-4.48 (m, 1H), 4.00-3.96 (m, 2H), 3.61 (s, 3H), 3.48-3.43 (m, 2H), 1.75-1.71 (m, 2H). LCMS: MH+ 555 and TR=3.087 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3].[CH:13]1([Mg]Br)[CH2:15][CH2:14]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[O:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:2]([CH:13]3[CH2:15][CH2:14]3)([OH:3])[CH3:1])=[CH:5][C:6]=2[O:12][CH2:11]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c(c1)OCO2)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (9.14 mmol) of 3,4-(methylenedioxy)acetophenone and 36.5 ml (18.28 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.32 g (70% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]N1C(=O)CCC1=O>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncnc(Cl)c1I

Procedure:
To a solution of 6-chloropyrimidin-4-amine (1 g, 7.8 mmol) in 5 mL N,N-dimethylformamide was added N-iodosuccinimide (2.6 g, 11.6 mmol) and the mixture subjected to microwave irradiation (Biotage Initiator) at 100° C. for 30 minutes. The mixture was diluted with water and ethyl acetate and the ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 25% ethyl acetate in hexane) afforded the title compound. LCMS: 255.91 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, 834 mg (5 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [for preparation see: Liebigs Ann. Chem., 1895 (1977)] are introduced into 10 ml of ethanol and, at 0-5° C., 358 mg (5 mmol) of sodium ethanolate are added thereto. The bright yellow suspension is stirred for 15 min and then 623 mg (2.5 mmol) of 2-bromo-1-(naphth-2-yl)-ethan-1-one (2-bromo-2'-acetonaphthone; Aldrich; Milwaukee/USA) are added thereto. After 3 days' stirring at RT, the reaction mixture is concentrated by evaporation. The residue is taken up in ethyl acetate/water and filtered and the organic phase is separated off and washed with 3 portions of water and brine. The aqueous phases are extracted with ethyl acetate and the organic phases are dried over MgSO4 and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diethyl ether/hexane yield the title compound; m.p. 149-151° C.; TLC-Rf =0.5 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =281.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1cccc(F)c1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1cccc(F)c1
Reaction time: 20 h

Procedure:
From 3-fluorobenzyl alcohol (5.1 g; 40 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 20 h at 100° C. The yield was 1.04 g (72%). Mp 115-119° C.