Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([CH2:20][C:21]([O:23]C)=[O:22])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])#[N:2].[Li+].[OH-].Cl>C1COCC1>[C:1]([C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([CH2:20][C:21]([OH:23])=[O:22])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])#[N:2]
Reactant: COC(=O)Cc1cn2c(-c3ccc(Cl)cc3Cl)c(C#N)c(C)nc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2nc(CC(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1C#N
Reaction time: 0.3 h
Yield: 94.5 %

Procedure:
To a solution of methyl 2-(6-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetate (Example 162, Step 4, 260 mg, 0.7 mmol) in THF (1.4 mL) was added LiOH (2.0 M in H2O, 7 mL, 14 mmol). After 18 min, the clear brown reaction was adjusted to pH 2 using hydrochloric acid (2 N in H2O, 2.35 mL, 4.7 mmol). The solution became less dark and a precipitate formed. The mixture was extracted with EtOAc (3×7 mL), the combined organic extracts were back-washed with 5 mL water, and then dried with MgSO4. Filtration and concentration provided 2-(6-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetic acid (239 mg, 95%) as a yellow-brown foam.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][C:40]=1[F:41])/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]4[CH:38]=[CH:39][C:40]([F:41])=[C:30]([F:29])[CH:31]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J (142 mg, 0.333 mmol), and trans-3,4-difluorocinnamic acid, by the method of Example 1, step K, giving a yellow solid for the more polar chromatographic product, which was still a mixture of stereoisomers by NMR and LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H34F2N4O2: 521 (M+H). Found: 521.2. 1H NMR (CHLOROFORM-d) δ: 7.95-8.03 (m, 1H), 7.62 (dd, J=7.7, 3.9 Hz, 1H), 7.55 (dd, J=15.4, 6.8 Hz, 1H), 7.30-7.39 (m, 2H), 7.06-7.24 (m, 4H), 6.90-7.02 (m, 1H), 6.75-6.86 (m, J=15.4, 6.1 Hz, 1H), 5.54 (d, J=3.5 Hz, 1H), 4.69-4.90 (m, 1H), 4.14 (br. s., 1H), 3.02-3.22 (m, J=15.4 Hz, 2H), 2.73-2.85 (m, 1H), 2.56-2.73 (m, 1H), 2.45 (tt, J=11.0, 3.4 Hz, 1H), 2.04-2.23 (m, 3H), 1.89-2.04 (m, 2H), 1.66-1.88 (m, 5H), 1.14-1.54 (m, 6H).
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[C:15](/[C:16](/O)=[CH:17]\[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[N:38]1([C:44](=[S:46])[NH2:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:9][C:10]1[C:15]([C:16]2[N:45]=[C:44]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[S:46][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: NC(=S)N1CCOCC1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Yield: 95 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using NBS (0.41 g, 2.29 mmol), N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (1.0 g, 2.18 mmol) and 4-morpholinecarbothioamide (0.35 g, 2.40 mmol) the title compound was obtained as a yellow solid (1.27 g; 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 8.31 (d, J=5.5 Hz, 1H), 7.28-7.75 (m, 8H), 6.20 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.54 (t, J=4.6 Hz, 4H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:34]=[CH:33][CH:32]=[CH:31][C:13]=3[C:14]([NH:16][CH:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:18]([OH:22])[C:19]([OH:21])=O)=[O:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:36][O:37][NH2:38]>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:17]([NH:16][C:14](=[O:15])[C:13]2[CH:31]=[CH:32][CH:33]=[N:34][C:12]=2[N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH:18]([OH:22])[C:19]([NH:38][O:37][CH3:36])=[O:21])=[CH:29][CH:28]=1
Reactant: O=C(NC(Cc1ccc(F)cc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccc(F)cc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-(4-fluorophenyl)-butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 490.1
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:14][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)[CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: CS(=O)(=O)Oc1ccc(CCCCS(=O)(=O)[O-])cc1
Reactant: CCOC(=O)C(Cc1cccc(O)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Yield: 64.6 %

Procedure:
Compound (c) (1.905 g; 6.18 mmole) was dissolved in acetonitrile (13 ml) and added dropwise to a mixture of ethyl 2-ethoxy-3-(3-hydroxyphenyl)-propanoate (1.47 g; 6.18 mmole) and potassium carbonate (2.56 g; 18.54 mmole) in acetonitrile (15 ml). The mixture was refluxed for 5 hours, then the solvent was evaporated in vacuo and water was added. The mixture was extracted twice with dichloromethane, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using diethyl ether/petroleum ether (gradient 33% to 100% diethyl ether) gave 1.80 g (yield 65%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:5](=[O:9])[C:4]=1[C:10]#[N:11]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccn(-c2ccncc2[N+](=O)[O-])c(=O)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (3.00 g), 4-chloro-3-nitropyridine (6.34 g), cesium carbonate (13.02 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hr. The reaction mixture was slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added isopropyl ether (20 mL), and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (5.00 g).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3[C:15]4=[C:16]([NH:20][C:21]5[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=5)[N:17]=[CH:18][N:19]=[C:14]4[S:13][C:10]=32)=[N:5]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]3[S:13][C:10]4[C:11]5[C:6]([CH2:7][CH2:8][C:9]=4[C:15]=23)=[N:5][N:4]([CH2:3][CH2:2][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[CH:12]=5)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CN1CCNCC1
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
To a stirring solution of 2-(2-bromoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (100 mg, 0.2 mmol) in DMF solution (5 mL) were sequentially added 1-methyl-piperazine (0.03 mL, 0.31 mmol), sodium iodide (31.3 mg, 0.21 mmol), and sodium carbonate (44.3 mg, 0.42 mmol). The mixture was stirred at 60° C. for 4 h, after which time the contents were allowed to cool to rt and the solvent then removed under reduced pressure. The crude product was purified via reverse phase HPLC to afford the desired product (66 mg, 63%) as a white solid. 1H-NMR (CD3OD) δ 2.25 (s, 3H), 2.40-2.60 (m, 8H), 2.76 (t, 2H), 2.95 (t, 2H), 3.28 (t, 2H), 4.17 (t, 2H), 7.10 (t, 1H), 7.45-7.50 (m, 1H), 7.69 (s, 1H), 7.84 (dd, 1H), 8.42 (s, 1H); LCMS RT=2.46 min; [M+H]+=498.2.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH2:15][Si](C)(C)C)=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][C:15]3[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=3)=[O:12])[CH:9]=2)[CH2:4][CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)[C@@H](O)CC2
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccccc1)c1ccc2c(c1)[C@@H](OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of the alcohol from Step 2 (140 mg, 0.503 mmol) was added NaH (28.2 mg, 1.18 mmol) in one portion at RT. After stirring for 30 min, BnCl (116 μL, 1.01 mmol) was added dropwise and the resulting mixture was stirred overnight. The excess NaH was quenched with water and the mixture was transferred to a seperatory funnel where the aqueous layer was washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to yield an oil. The title compound was purified on a Biotage MPLC (grad: 100% Hex to 60% EtOAc in Hex).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.[NH2:55][C:56]1[O:57][CH:58]=[CH:59][N:60]=1>CN(C)C=O>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([NH:55][C:56]2[O:57][CH:58]=[CH:59][N:60]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncco1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncco1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 47 %

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.23 mmol), 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 60 mg, 0.21 mmol), N,N-diisopropylethylamine (73 μL, 0.42 mmol), and 2-aminooxazole (27 mg, 0.31 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide (34.9 mg, 47%) as a white solid: mp 134-136° C.; EI-HRMS m/e calcd for C17H18Cl2N2O2(M+) 352.0745, found 352.0750.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:16][CH2:15]1>CCO.[Pt]>[CH3:1][C:2]1[C:3]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:19]2)=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:7]=1)[NH2:8]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
1-[2-Methyl-5-(ethyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (9.7 g, 26 mmol) was taken up in EtOH (100 mL). The catalyst, 5% sulfided platinum on carbon (1.0 g) was added. The reaction was placed under 1 atm of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated onto silica in vacuo. The product was purified on a 120 g ISCO column (DCM to 2% (2N NH3 in MeOH) to give the title compound of Step B (1.9 g, 5.7 mmol, 22%) as a pale orange oil. The mixed fractions (product and starting material) were resubmitted to the above conditions to provide additional product (5.2 g, 15 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 6.52 (s, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.56 (s, 2H), 3.15 (t, J=6.3 Hz, 2H), 3.05 (s, 3H), 2.91 (t, J=6.4 Hz, 2H), 2.84-2.78 (m, 4H), 2.67-2.54 (m, 4H), 2.13 (s, 3H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:3]1
Reactant: Clc1cnccn1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2cnccn2)(c2ccccc2)CC1
Yield: 11.1 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM), in DMSO (100 ml) was treated with 50% sodium hydride dispersion (2.0 g, 40 mM) and the mixture warmed to 80° until a clear solution was obtained. After cooling to room temperature a solution of 2-chloropyrazine (5.6 g, 40 mM) in DMSO (10 ml) was added. After 48 hours the reaction mixture was poured on to water (400 ml), extracted with ether (3×250 ml), the organic phase dried and the solvents removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave recovered 1-methyl-4-phenyl-4-piperidinol (2 g). Chromatography of the mother liquors on Grade III silica using 3% methanol in chloroform as eluant, evaporation of the appropriate fractions and recrystallisation from pentane gave the title compound (1.2 g) m.p. 115°-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[Cl:12]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[Cl:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)O)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
A mixture of 4-methoxybenzoic acid (0.46 g; 3 mmol) and N-chlorosuccinimide (NCS) (0.36 g; 2.7 mmol) in trifluoroacetic acid (5 ml) was stirred for 3 h at ˜70° C. After removing solvent under reduced pressure the residue was treated with H2O (10 ml). The solid was filtered off and purified by FCC (SiO2; EtOAc) to give the title compound (0.38 g; 68%) as a colourless solid. 1H-NMR (CDCl3) 3.97 (s, 3H); 6.96 (d, 1H, J=8.7 Hz); 8.0 (dd, 1H, J=2; 8.7 Hz); 8.11 (d, 1H, J=2 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Br[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[O:17]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=3)[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])[CH2:9][C:7]=2[N:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Br)c1
Reactant: CSc1ncc2c(n1)CNC2
Product: CSc1ncc2c(n1)CN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2

Procedure:
In a manner similar to that describe in Example 126, 2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine and 3-Bromo-N-[3-(trifluoromethyl)phenyl]benzamide were converted to the title compound.
Reaction SMILES: [CH:1]1([C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[OH-].[Na+]>CO>[CH3:10][O:9][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([C:11]([OH:13])=[O:12])[CH2:2]1)=[O:8]
Reactant: COC(=O)C1CCCC(C(=O)OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CCCC(C(=O)O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a solution of 1,3-cyclohexanedicarboxylic acid (10 g, 58 mmol) in MeOH (50 mL) was added conc. H2SO4 (2 mL). Then the mixture was stirred at room temperature for 4 hrs. The mixture was concentrated under reduced pressure, and then partitioned between ethyl acetate and a saturated aqueous NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, and evaporated to give dimethyl 1,3-cyclohexanedicarboxylate as a colorless oil (11.6 g, yield; quant.). To a solution of dimethyl 1,3-cyclohexanedicarboxylate (11.6 g, 57.9 mmol) in MeOH (58 mL) was added a 1N NaOH solution (58 mL) dropwise over 1 hr at 0° C. The resulting mixture was stirred at 0° C. for 0.5 hrs, and at room temperature for 2 hrs. The mixture was concentrated under reduced pressure, and the residual solution was partitioned between ethyl acetate and water. The aqueous phase was separated, acidified with conc. HCl (15 mL), saturated with NaCl, and then extracted with ethyl acetate. The extract was dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(methoxycarbonyl)cyclohexanecarboxylic acid as a colorless oil (6.16 g, yield; 57%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[F:13][C:14]([F:32])([C:28]([F:31])([F:30])[F:29])[C@@H:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1)[CH3:16].CCN(CC)CC.CCOC(C)=O>C(O)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([O:17][C@H:15]([C:14]([F:13])([F:32])[C:28]([F:30])([F:31])[F:29])[CH3:16])=[O:27])=[CH:24][CH:23]=1
Reactant: C[C@H](OC(=O)c1ccc(C=O)cc1)C(F)(F)C(F)(F)F
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](OC(=O)c1ccc(Cc2c(O)c3ccccc3oc2=O)cc1)C(F)(F)C(F)(F)F
Temperature: 140 °C
Reaction time: 4 h

Procedure:
4-Hydroxycoumarin (1.367 g, 8.44 mmol) and (S)-4-formyl-benzoic acid 2,2,3,3,3-pentafluoro-1-methyl-propyl ester (2.505 g, 8.46 mmol) were dissolved in formic acid (3.0 mL) and Et3N (3.6 mL) at 0° C. After stirring at 140° C. for 4 h, the yellow solution was cooled to rt, EtOAc was added, and the organic layer was washed successively with 1 N HCl and brine. After drying over Na2SO4 and concentrating, the pale yellow solid was purified twice by silica gel chromatography (DCM:MeOH 100:6 and DCM:MeOH 100:5) to yield the title compound in 92.5% ee as determined by chiral HPLC.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[N:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C:17](=[O:22])[C:16]=2[CH:15]=[N:14][CH:13]=1>CCCCC.O1CCCC1.CN(C)C=O.[Cl-].[Na+].O>[N:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C:17]3([CH2:8][O:22]3)[C:16]=2[CH:15]=[N:14][CH:13]=1
Reactant: O=C1CCCc2ncncc21
Reactant: C[S+](C)C
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCCCC
Solvent: CN(C)C=O
Product: c1ncc2c(n1)CCCC21CO1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (22 mmol) washed with pentane is admixed under argon with 20 ml of dimethyl sulphoxide. The mixture is heated at 60° C. for an hour and then diluted with 5 ml of tetrahydrofuran. The mixture is cooled to 0° C., a solution of 21 mmol of trimethylsulphonium iodide in 5 ml of N,N-dimethylformamide is added at 0° C., and the mixture is stirred for 10 minutes. A solution of 20 mmol of 7,8-dihydro-6H-quinazolin-5-one [21599-28-0] in 5 ml of N,N-dimethylformamide is added and the reaction mixture is stirred at 20-60° C. for 18 hours. The reaction mixture is poured into cold brine and extracted with tert-butyl methyl ether. The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]([F:28])([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:17]2[C@@H:8]([O:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16]2)[CH2:7][C@H:6]1[OH:19].C(N(CC)CC)C.[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39]([C:42](Cl)=[O:43])=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CN(C)C1C=CN=CC=1>[C:45]1([C:36]2[CH:37]=[CH:38][C:39]([C:42]([O:19][C@@H:6]3[CH2:7][C@@H:8]4[O:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][C@@H:17]4[C@H:5]3/[CH:4]=[CH:3]/[C:2]([F:1])([F:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:43])=[CH:40][CH:41]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (8aR,9R,10R,11aS,Z)-9-((E)-3,3-difluoro-4-phenoxybut-1-en-1-yl)-10-hydroxy-4,5,8,8a,9,10,11,11a-octahydrocyclopenta[b]oxecin-2(3H)-one (20.0 g, from Example 34) in THF (200 mL) was treated with triethylamine (20.6 g, 0.20 mol), 4-(dimethylamino)pyridine (0.62 g, 5.09 mmol) and biphenyl-4-carbonyl chloride (33.0 g, 0.15 mol). This mixture was then stirred for 18 hr at room temperature under an atmosphere of nitrogen. Saturated aqueous solution of sodium bicarbonate (200 mL) was poured into the reaction mixture and the resulting mixture was stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were dried over magnesium sulfate, the solid was filtered off and filtrate was concentrated under reduced pressure to give 40.0 g of crude product. The crude product was purified by column chromatography and then concentrated under reduced pressure to provide 20.0 g of the title compound (69.0% yield). The residue was crystallized from methanol to give white crystalline compound (mp 105˜109° C.). The x-ray powder diffraction pattern of crystalline title compound has characteristic peaks expressed in degrees 2θ at approximately 5.0, 6.2, 7.6, 9.5, 10.1, 11.5, 12.6, 13.7, 15.2, 18.0, 19.4, 21.2, 23.1, 23.6, 24.4, 25.7, 28.0, 37.9, 44.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1.[CH2:23](I)[CH3:24]>>[CH2:23]([N:9]1[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7](=[O:21])[C:8]1=2)[CH3:24]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Product: CCOC(=O)c1cn(CC)c2c(=O)c3cc(Cl)ccc3oc2c1=O
Yield: 77.6 %

Procedure:
Prepared from ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (3.19 g, 0.01 mole) and ethyl iodide (6.24 g, 0.04 mole) by the method described for Example 9. Recrystallization from DMF gave white crystals (2.7 g, 78%), m.p. 257°-259°.