Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([PH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[P:16]([CH2:29][CH2:30][CH2:31]Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Li]>C1COCC1.O>[P:16]([CH2:29][CH2:30][CH2:31][PH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCCP(c1ccccc1)c1ccccc1
Reactant: Pc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(PCCCP(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
In a Schlenk flask were placed phenylphosphine (3.3806 g, 30.71 mmol) with THF (60 ml) and chilled to −30° C. in a freezer over 30 minutes. To this solution was added lithium diisopropylamide (16 ml, 32.16 mmol) and the resulting solution was allowed to warm to room temperature while stirring. In a 250 ml Schlenk flask was placed (C6H5)2P(CH2)3Cl (7.9089 g, 30.1 mmol) in 100 ml THF and the solution was cooled to −78° C. The lithium phenylphosphide solution was added to the (C6H5)2P(CH2)3Cl solution at such a rate that the temperature of the solution remained constant at −78° C. After addition, the solution was slowly warmed to room temperature. Degassed DI water (0.2 ml) was added to the dark orange solution. The color changed to yellow-orange. The solvents were removed in vacuo. The resulting gel was dissolved in toluene and filtered through Celite. Toluene was then removed in vacuo, leaving an orange-yellow oil. Yield: 10.0 g (99.1%). 31P{1H} NMR (CDCl3, 122 MHz, δppm: −16.30 and −52.86 (>99% pure). 1H NMR (CDCl3, 400 MHz, δ: 1.58–2.15 (3 complex peaks integrated to ˜7Hs), 4.12 (d of t, H—P) and 7.26–7.43 (complex pattern).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH3:30])[CH:22]=1.CO>COCCOC>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][C:16]#[N:17])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(Br)ccc1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of potassium tert-butoxide (6.5 g, 0.058 mol) in 1,2-dimethoxyethane (150 mL) was added p-toluenesulfonylmethyl isocyanide (5.6 g, 0.029 mol) portionwise at −78° C. Then a solution of 4-bromo-2-methoxybenzaldehyde (6.3 g, 0.029 mol) in 1,2-dimethoxyethane was added dropwise and the reaction mixture was warmed to room temperature. The mixture was stirred at room temperature for 1 hour and methanol (150 mL) was added, then heated to reflux and stirred for 2 hours. Solvent was evaporated, and saturated ammonium chloride (100 mL) was added and extracted with ethyl acetate (100 mL×2). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by combiflash (Petroleum ether/EtOAc=10:1 to 5:1) to give the title compound (5.4 g, 82%) as a light yellow solid.
Reaction SMILES: C([N:5](CCCC)CCCC)CCC.[CH:14]1[C:20](=O)[NH:19][C:17](=O)[N:16]([C@@H:22]2[O:26][C@H:25]([CH2:27][O:28][P:29]([O:32][P:33]([OH:36])([OH:35])=[O:34])([OH:31])=[O:30])[C@@H:24]([OH:37])[C@H:23]2[OH:38])[CH:15]=1.[CH:39]1[C:45](=[O:46])[NH:44][C:42](=[O:43])[N:41]([C@@H:47]2[O:51][C@H:50]([CH2:52][O:53][P:54]([O:57][P:58]([O-:61])([OH:60])=[O:59])([O-:56])=[O:55])[C@@H:49]([OH:62])[C@H:48]2[OH:63])[CH:40]=1.[Na+].[Na+]>CCO>[P:29]([O:28][CH2:27][C@H:25]1[O:26][C@@H:22]([N:16]2[C:15]3[N:44]=[CH:42][N:41]=[C:20]([NH2:19])[C:14]=3[N:5]=[CH:17]2)[C@H:23]([OH:38])[C@@H:24]1[OH:37])([O:32][P:33]([OH:35])([OH:36])=[O:34])(=[O:30])[OH:31].[CH:39]1[C:45](=[O:46])[NH:44][C:42](=[O:43])[N:41]([C@@H:47]2[O:51][C@H:50]([CH2:52][O:53][P:54]([O:57][P:58]([OH:60])([OH:61])=[O:59])([OH:56])=[O:55])[C@@H:49]([OH:62])[C@H:48]2[OH:63])[CH:40]=1
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)([O-])OP(=O)([O-])O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCN(CCCC)CCCC
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Na+]
Solvent: CCO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
ADP (Bu3NH+)2, AMP (Bu3NH+)2 and UMP (Bu3NH+)2 were prepared from the corresponding free acid and tributylamine (Bu3N; 2 eq) in EtOH. UDP (Bu3NH+)2 was prepared from UDP disodium salt. The latter salt was passed through a column of activated Dowex 50WX-8 200 mesh, H+ form. The column eluate was collected in an ice-cooled flask containing (Bu3N (2 eq) and EtOH. The resulting solution was freeze-dried to yield UDP (Bu3NH+)2 as a viscous oil.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH3:24][O:23][C:22]1[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]=2[CH:21]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1ccccc1-c1cc2c(cc1OC)N(C)C(=O)CN=C2c1cccc(C#N)c1
Yield: 50 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used o-methoxyphenyl boronic acid. The title compound (80 mg) was obtained as a white solid, in 50% yield.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH:42]=O)[CH:33]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:42][C:34]4[CH:33]=[N:32][C:41]5[C:36]([CH:35]=4)=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4cnc5ccccc5c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added quinoline-3-carboxaldehyde (13 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.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>[F:8][C:3]1[C:2]([C:11]2[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1C=CCCC1
Reactant: Fc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2F)CCC1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-2-fluoropyridine (11 g, 62.5 mmol), 2-cyclohexen-1-one (24.03 g, 250 mmol), N,N-dicyclohexylmethylamine (30.5 g, 156 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.958 g, 1.875 mmol) in dioxane (80 mL) was heated to 105° C. for 6 h. The mixture was cooled to RT and the dioxane was evaporated under reduced pressure. Water (200 ml) was added and the mixture layer was extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc in hexanes) afforded 3-(2-fluoropyridin-3-yl)cyclohex-2-enone as colorless crystals. MS (ESI, pos. ion) m/z: 191.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[NH:16][N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[F:36][C:37]([F:43])([F:42])[CH2:38][CH2:39][CH2:40]I>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[N:16]([CH2:40][CH2:39][CH2:38][C:37]([F:43])([F:42])[F:36])[N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1
Reactant: FC(F)(F)CCCI
Reactant: O=C(CNc1ccn[nH]c1=O)N1CCC(Oc2cc(C(F)(F)F)ccc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CNc1ccnn(CCCC(F)(F)F)c1=O)N1CCC(Oc2cc(C(F)(F)F)ccc2Cl)CC1
Yield: 67 %

Procedure:
Compound 45 is prepared following synthesis method 6: 0.3 g (0.7 mmol) of intermediate 7b are placed in 10 mL DMF in the presence of 0.13 g (0.94 mmol) K2CO3 then 0.222 g (0.90 mmol) of 1,1,1-trifluoro-4-iodo-butane and agitated at 80° C. for 32 h. After concentrating to dryness, the residue is solubilized in water and extracted with AcOEt. The organic phases are washed in brine, dried over Na2SO4 then concentrated to dryness. The residue is purified by silica gel flash chromatography (gradient CH2Cl2-MeOH: 100:0 to 99:1 for 30 nm). 0.250 g of compound 45 are collected (yield: 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NC(C)C)s1
Yield: 51 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (42 mg, 51%) which was obtained as a white solid. MS: m/e=375.3 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][N:26]([CH3:32])[C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH3:25][N:26]([CH3:32])[C@@H:27]1[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:28]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CN(C)[C@@H]1CCN(CCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)C1

Procedure:
The product from Example 1C and 3-(R)-(dimethylamino)pyrrolidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 360 (M+H)+;
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12]2[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:27])=[O:2])[C:10](=[O:26])[CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(CC(C)(C)O)cc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(CC(C)(C)O)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 83 %

Procedure:
A solution of (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.150 g, 0.40 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.017 g 0.40 mmol). The mixture was stirred at room temperature for 1.75 h and then partitioned between ethyl acetate and water. The water layer was made acidic with 1N aqueous hydrochloric acid (pH=1) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.120 g, 83%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][N:41]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:43]4[CH:42]=[N:41][C:40]([O:39][CH3:38])=[N:45][CH:44]=4)=[CH:31][CH:30]=3)[C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(Cn3c(C4CCCCC4C(=O)O)nc4cc(OCc5nc6ccccc6s5)ccc43)cc2)cn1

Procedure:
The title compound was prepared using analogous conditions described in Step A of Example 97 using racemic cis-2-(5-(benzo[d]thiazol-2-ylmethoxy)-1-(4-bromobenzyl)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and (2-methoxypyrimidin-5-yl)boronic acid. MS (ESI): mass calcd. for C34H31N5O4S, 605.72; m/z found, 606.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.77-8.72 (s, 2H), 8.01-7.91 (m, 2H), 7.60-7.53 (d, J=8.3, 2H), 7.53-7.48 (m, 1H), 7.45-7.39 (ddd, J=8.2, 7.2, 1.2, 1H), 7.36-7.30 (d, J=2.4, 1H), 7.28-7.23 (d, J=8.3, 2H), 7.23-7.19 (d, J=8.9, 1H), 7.02-6.95 (dd, J=8.8, 2.4, 1H), 5.62-5.47 (m, 4H), 4.03-4.00 (s, 3H), 3.64-3.57 (m, 1H), 2.90-2.81 (dt, J=7.3, 4.1, 1H), 2.45-2.31 (qd, J=7.6, 3.6, 1H), 2.08-2.02 (m, 1H), 1.93-1.81 (m, 2H), 1.81-1.71 (m, 2H), 1.51-1.41 (d, J=14.1, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[O:25])[C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20]>CO.C1COCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([CH2:14][CH2:15][N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[O:25])[C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: C=CS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A 2M solution of dimethylamine (0.06 ml) in anhydrous methanol was added to a deoxygenated solution of (R)-N-[2-chloro-4-(ethenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 283) (0.044 g) in anhydrous THF (1 ml). The mixture was allowed to stir at ambient temperature under argon for 2 hours then volatile material was removed by evaporation to give the title compound (in 89% yield) as a solid. NMR: 1.69 (s, 3H), 2.65 (s, 6H), 2.55 (t, 2H), 3.55 (t, 2H), 7.9 (d, 1H), 8.08 (s, 1H), 8.34 (d, 1H); MS (ESP−): 403.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(#N)C>[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]([C:5]3[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)CNC(=O)COc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: COC(=O)CNC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl N-[4-(bromoacetyl)phenoxyacetyl]glycinate (0.85 g) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (0.81 g) in acetonitrile (30 ml). After stirring overnight the solvent was removed in vacuo and the residue partitioned between water/ethyl acetate. The organic phase was washed with water, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica, eluting with 0 to 7.5% v/v methanol/dichloromethane. Evaporation of the fractions gave the title compound, 130 mg, as a foam: NMR (d6DMSO) δ8.58 (1H, t), 8.16 (2H, d), 8.01 (2H, d), 7.08 (2H, d), 6.83 (2H, d), 5.75 (1H, s), 4.68 (2H, s), 3.92 (2H, d), 3.84 (2H, s), 3.65 (3H, s), 3.34 (4H, t+H2O), 2.65 (4H, t); m/e 427 (M+H)+ ; calculated for C22H26N4O5. 0.5CH2Cl2 : C, 57.6; H, 5.8; N, 11.9. found: C, 57.8; H, 5.7; N, 12.0%.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[C:41]1([CH2:51][C@H:52]([CH2:56][C:57]([N:59]2CCO[CH2:61][CH2:60]2)=[O:58])C(O)=O)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1.P(C#N)([O:70][CH2:71][CH3:72])(OCC)=O.C(N(CC)CC)C>>[C:41]1([CH2:51][C@H:52]([CH2:56][C:57]([N:59]2[CH2:72][CH2:71][O:70][CH2:61][CH2:60]2)=[O:58])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([C:27]([CH2:28][CH3:29])([OH:30])[CH2:31][CH3:32])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(=O)NC
Solvent: CCN(CC)CC
Product: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(=O)NC
Yield: 86.6 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 120 mg (0.21 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-ethyl-1-hydroxypropyl)-N-methylhexanamide [prepared as described in Example 18(a)], 81 mg (0.25 mmoles) of 2(R)-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionic acid, 0.04 ml (0.26 mmoles) of diethyl cyanophosphate, and 0.09 ml (0.65 mmoles) of triethylamine were used, to obtain 144 mg (yield 88%) of the title compound as a white amorphous substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-])=O>O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: C1COCCO1
Product: Nc1ccc(C(=O)O)c(C(=O)O)c1
Yield: 50 %

Procedure:
124.9 g (0.69 mol) of 4-aminophthalic acid freshly obtained by reduction of 4-nitrophthalic acid in dioxane are reacted with 109.8 g (0.72 mol) of cis-1,2,3,6-tetrahydrophthalic anhydride in the manner described in Example 9, and the product is worked up as follows: after the batch has stood for 20 hours, the clear reaction solution is concentrated in vacuo to approx. 200 ml and heated with 200 ml of acetic anhydride and 170 ml of pyridine to 60° C. for 10 hours. The solvents are then stripped off in vacuo and the solid residue is recrystallised from benzene, whereupon the yellow-coloured phthalic anhydride derivative is obtained in a yield of about 50%, melting point = 188° C.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:5]=1[CH2:6][O:7][C:8]1[C:9]2[N:10]([C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14].Cl>C1COCC1.C(O)C>[F:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:5]=1[CH2:6][O:7][C:8]1[C:9]2[N:10]([C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)c(F)ccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.14 ml (1.14 mmol) of 1 N lithium hydroxide solution were added to 365 mg (0.76 mmol; purity about 76%) of ethyl 8-[(2,6-difluorobenzyl)oxy]-7-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate Example 269A in 16.6 ml of THF/ethanol (5/1), and the mixture was stirred at RT overnight. Another 2.67 ml (2.67 mmol) of 1 N lithium hydroxide solution were added and the mixture was stirred at RT overnight. Under reduced pressure, the reaction mixture was freed from organic solvent, and the aqueous phase was acidified to pH 4 with 6 N hydrochloric acid whilst cooling with ice water. The solid formed was filtered off and dried under high vacuum. This gave 236 mg of the target compound (87% of theory, purity 94%).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13](OCC)=[O:14].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:3]1([C:2]2[N:10]=[C:13]([OH:14])[CH:12]=[C:11]([OH:18])[N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Oc1cc(O)nc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of benzamidine hydrochloride (44.41 g; 0.284 mol), diethyl malonate (45.51 g; 0.284 mol) and DBU (86.40 g; 0.568 mol) in DMF (250 mL) was heated at 85° C. for 20 h. After cooling to room temperature, the flask was placed in a refrigerator overnight. The crystalline product was collected by filtration and washed with DMF (300 mL), then dissolved in water (ca. 110 mL) and acidified with 2 M HCl (110 mL) with water added, as necessary, to maintain a suspension. The product was collected by filtration, washed with water (100 mL) and dried to a constant weight under high vacuum giving 39.09 g (73%) of an off-white solid. LC (method B) tR=6.2 min; 1H NMR (200 MHz, DMSO-d6) δ 8.08 (m, 2H), 7.54 (m, 3H), 5.34 (s, 1H); ESIMS 189.0 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26](OC)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:31]>CO>[CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:30])[CH2:22][S:23][CH2:24][CH2:25][C:26]([NH2:31])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Reaction time: 168 h

Procedure:
1 g of methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate (Example 1) is dissolved in 20 ml of an approximately 10% strength solution of ammonia in methanol, and the solution is left to stand in a closed vessel at room temperature for 7 days. The solvent is removed by distillation in vacuo, and the residue is purified by column chromatography on silica gel (mobile phase ethyl acetate/cyclohexane 1:4).