Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=4[Cl:30])(=[O:19])=[O:18])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:32]=[CH:31][C:5]=3[N:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:19]
Reactant: Nc1ccc2nc(Oc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3)sc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc2nc(Oc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3)sc2c1

Procedure:
2-Chloro-N-[4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide was synthesized from N-[4-(6-amino-benzothiazol-2-yloxy)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide (448) and methanesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.82 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.16 (d, J=1.1 Hz, 1H), 7.95 (dd, J=8.3, 1.2 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.37-7.34 (m, 2H), 7.24 (dd, J=8.7, 2.2 Hz, 1H), 7.23-7.19 (m, 2H). MS (EI): m/z 576 (M−H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([CH:12]2[CH2:17][CH2:16][C:15]([OH:26])([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[CH2:9]1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[NH2:7][CH:8]1[CH2:9][N:10]([CH:12]2[CH2:13][CH2:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)([OH:26])[CH2:16][CH2:17]2)[CH2:11]1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)OC(C)(C)C)C3)CC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(N)C3)CC2)cn1

Procedure:
{1-[4-Hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-carbamic acid tert-butyl ester (less polar isomer from Step A, 5.50 g, 14.6 mmol) in DCM (10 mL) and TFA (10 mL) at room temperature was stirred for 2 hours. The solvent was removed and dried under vacuum to give the title compound as colorless oil.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[C@H:17]([C:31]([O-:33])=O)[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:35][C@@H:36]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].F[P-](F)(F)(F)(F)F.CN([C+](N(C)C)N1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:49]([O:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][C@H:36]([NH:35][C:31]([C@@H:17](/[CH:16]=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:33])[C:37]([O:39][CH3:40])=[O:38])=[CH:43][CH:44]=1)[C:50]#[C:51][CH3:52]
Reactant: CCCCCCCSCCCCCC/C=C/[C@H](C(=O)[O-])[C@@](O)(CCOC)C(=O)OC(C)(C)C
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Agent: CN(C)[C+](N(C)C)n1n[n+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCSCCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, at room temperature, to 1-tert-butyl (2S,3S)-3-((E)-8-heptylsulfanyl-oct-1-enyl)-2-hydroxy-2-(2-methoxy-ethyl)-succinate (210.0 mg, 0.430 mmol) obtained in Step C-6b in DMF (4.2 mL), were added methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate hydrochloride (148.4 mg, 0.516 mmol), 1-[bis(dimethylamino)methyliumyl]-1H-1,2,3-triazolo[4,5-B]pyridine-3-oxide hexafluorophosphate (179.1 mg, 0.473 mmol), and N,N-diisopropylethylamine (299.0 μL, 1.72 mmol) in order. After stirring for 8 hours, the progress of the reaction was stopped by adding water. The mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was then washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled out of the filtrate under reduced pressure. The resulting residue was purified with SP1 (SiO2 cartridge, 20% ethyl acetate/n-hexane, Rf=0.35) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804240; 249.3 mg, 2 steps, 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:8]=[C:7]([Cl:12])[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(Cl)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(3-Chloro-5-hydroxy-phenyl)-acetic acid methyl ester (2.9 g, 14.5 mmol), 2-fluoro-5-nitrobenzaldehyde (2.7 g, 15.9 mmol), and potassium carbonate (4.0 g, 28.9 mmol) were combined in 1,4-dioxane (20 mL) and stirred at 100° C. overnight. Once no starting material was seen by analytical LCMS and tlc, the mixture was worked up with EtOAc and 10% aqueous HCl, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH3:31])[C:24]([I:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27].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>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:22]=[C:23]([CH3:31])[C:24]([I:30])=[C:25]([CH:29]=1)[C:26]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:27]
Reactant: Cc1cc(F)cc(C(=O)O)c1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)cc(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (1.2 eq.), 5-fluoro-2-iodo-3-methylbenzoic acid (1 eq.), DIPEA (3 eq.), and HATU (1 eq.) in DMF (0.2 M) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. NaHCO3 and brine. The organic layer was separated, dried with MgSO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound.
Reaction SMILES: CC1(C)C2C(=C[C:8]([C:12](=[O:14])C)=CC=2)C(=O)CC1.[CH3:17][C:18]1([CH3:32])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[O:30])[CH3:29])[CH:26]=2)[C:21](=[O:31])[CH2:20][CH2:19]1.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:29][C:28]1([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:31])[CH2:20][CH2:19][C:18]3([CH3:32])[CH3:17])[O:14][CH2:12][CH2:8][O:30]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CCC(=O)c2ccc(C3(C)OCCO3)cc21
Temperature: 25 °C

Procedure:
A solution of 1.80 g (8.34 mmol) of a 1:5 mixture of 3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (Compound D14a); and 3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (Compound D14b) in 50 mL benzene was combined with 517.7 mg (8.34 mmol) of ethylene glycol and 20.0 mg (0.11 mmol) of p-toluenesulfonic acid monohydrate. The resulting solution was heated to reflux for 18 h, cooled to room temperature, and concentrated under reduced pressure. The title compound was isolated by column chromatography (10% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: C([Li])CCC.CN1CCNCC1.[C:13]1([C:19]2[C:20]([CH:24]=[O:25])=[CH:21][O:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Li])(CC)C.Cl[Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34]>CCCCCC.O1CCCC1.C1CCCCC1>[C:13]1([C:19]2[C:20]([CH:24]=[O:25])=[CH:21][O:22][C:23]=2[Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=Cc1cocc1-c1ccccc1
Agent: CN1CCNCC1
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CC[Si](CC)(CC)c1occ(C=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (a 1.42M solution in hexane, 2.33 ml, 3.31 mmol) was added to a solution of 1-methylpiperazine (331 mg. 3.31 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon. After 15 minutes the solution was cooled to -78 degrees and 4-phenyl-3-furaldehyde. (517 mg, 3.01 mmol) was added. This mixture was warmed to 0 degrees and stirred for 15 minutes, then recooled to -78 degrees before sec-butyllithium (a 1.3M solutin in cyclohexane, 2.77 ml, 3.61 mmol) was added dropwise. This solution was stirred 12 hours at -78 degrees C. before chlorotriethylsilane (1.81 g, 12.02 mmol) was added. The mixture was allowed to warm gradually to room temperature and stirred an additional 11/2 hours. The reaction was quenched with ice-cold 5% (V/V) hydrochloric acid and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 10% ethyl acetate/hexanes to give the title aldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].Cl[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1ccc(Sc2ccccn2)cc1
Temperature: 140 °C
Yield: 42.2 %

Procedure:
A mixture of 18.4 g of 2-pyridinethiol, 23.2 g of 4-chlorobenzaldehyde, 40 g of potassium carbonate and 100 ml of hexamethylphosphoramide was heated at a temperature of 140° C. for 4 hours. After cooling, the mixture was filtered and the filtrate was concentrated. The resulting oily substance was dissolved in diethyl ether and the solution was washed successively with an aqueous solution of sodium hydroxide and water, and dried over magnesium sulfate. The solvent was distilled off and the resulting oily substance was distilled under reduced pressure to obtain 15 g (42% yield) of 4-(2-pyridylthio)benzaldehyde as a colorless oil having a boiling point of 136° C./2 mmHg.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([CH:23]3[CH2:22][CH2:21][N:20]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:25][CH2:24]3)=[CH:34][CH:33]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: O=C(O)c1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: N#CCNC(=O)C1(N)CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1(NC(=O)c2ccc(C3CCN(C4CCCC4)CC3)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.74 mmol), 4-(1-cyclopentyl-piperidin-4-yl)-benzoic acid hydrochloride (0.74 mmol), HOBT (0.74 mmol), WSCD (0.74 mmol) and triethylamine (0.74 mmol) are dissolved in DMF (5 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 233-234° C., Rf=0.34 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 636.24 (100) [MH+]; HPLC: tR=1.05 min (UPLC, purity).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26](=[O:45])[C@@H:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:36])[CH3:34])[CH:28]([CH3:30])[CH3:29])[CH:20]=2)[CH:7]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:40]([O:39][C:37]([N:35]([CH3:36])[C@@H:33]([CH3:34])[C:32]([NH:31][C@@H:27]([CH:28]([CH3:29])[CH3:30])[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C:19]1[CH:20]=[C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH:16]=[N:17][CH:18]=1)=[O:45])=[O:44])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)c1cn(-c2cncc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1c1cncc(-n2cc(C(=O)O)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
To a solution of 1-[5-((S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-pyrrolidin-2-yl)-pyridin-3-yl]-1H-indole-3-carboxylic acid ethyl ester (I-2A-2c: 0.29 g, 0.46 mmol) in THF (1 mL) and MeOH (0.3 mL) was added a solution of LiOH (0.035 g, 0.80 mmol) in water (0.3 mL). The resulting mixture was stirred at room temperature for 5 hours. More LiOH (0.065 g, 2.70 mmol) was added and stirring continued for overnight. The reaction mixture was then concentrated under reduced pressure to remove all organic solvents, then diluted with water. To this mixture 1 M HCl was added dropwise until pH=4. The white precipitate formed was filtered and dried in vacuo to give the titled compound as a white powder (0.19 g, 70%).
Reaction SMILES: N1C=CC=C(CN)C=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[C:26]2=[O:40])=[CH:22][CH:21]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:37]([C:33]1[S:32][C:31]([N:27]2[CH2:28][C@@H:29]([CH3:30])[N:25]([CH2:24][C:23]3[CH:41]=[CH:42][C:20]([F:19])=[CH:21][CH:22]=3)[C:26]2=[O:40])=[N:35][C:34]=1[CH3:36])=[O:38]
Reactant: NCc1ccc(F)c(F)c1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)c(F)c1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with 3,4-difluorobenzylamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 134-135° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=5.9 Hz, 1H), 7.44-7.30 (m, 4H), 7.21-7.12 (m, 3H), 4.60 (d, J=15.6 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.0, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.0, 6.8 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8](=[O:25])[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][O:21]C(=O)C)[C:11]=2[C:12]=1[OH:13].C(OC1C(=O)OC2C=CC=C(OCCOC(=O)C)C=2C=1O)C>>[CH3:1][CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8](=[O:25])[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][OH:21])[C:11]=2[C:12]=1[OH:13]
Reactant: CC(=O)OCCOc1cccc2oc(=O)c(OCCCC(C)C)c(O)c12
Agent: CCOc1c(O)c2c(OCCOC(C)=O)cccc2oc1=O
Product: CC(C)CCCOc1c(O)c2c(OCCO)cccc2oc1=O

Procedure:
In the same manner as in Example 1, except that an equimolar amount of 3-(4-methylpentyloxy)-4-hydroxy-5-(2-acetoxyethoxy)-2H-1-benzopyran-2-one was used in place 3-ethoxy-4-hydroxy-5-(2-acetoxyethoxy)-2H-1-benzopyran-2-one in Example 1, the titled compound was obtained.
Reaction SMILES: CO[C:3](=O)[C@@H:4](C)[NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([Cl:13])[N:7]=1.[CH3:16][Mg]Br.[Cl-].[NH4+].C([O:23][CH2:24][CH3:25])C>C1COCC1.O>[Br:12][C:11]1[C:6]([NH:5][C@H:4]([CH3:3])[C:24]([CH3:25])([OH:23])[CH3:16])=[N:7][C:8]([Cl:13])=[N:9][CH:10]=1
Reactant: COC(=O)[C@@H](C)Nc1nc(Cl)ncc1Br
Reactant: CCOCC
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
An ice-cooled solution of 2.95 g (10.0 mmol) of methyl-N-(5-bromo-2-chloropyrimidin-4-yl)-D-alaninate in 150 ml of THF is mixed drop by drop with 30 ml (90 mmol) of a 3 molar solution of methylmagnesium bromide in diethyl ether. After 2.5 hours at room temperature, the batch is mixed with 30 ml of saturated ammonium chloride solution. It is diluted with water and extracted from ethyl acetate (3×). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 4: 1-1:1). 2.81 g (9.5 mmol, corresponding to 95% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:7]([CH2:20][Cl:21])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:24]1[O:28][C:27]2[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:26]=2[O:25]1.Cl.[CH2:35](N1CC[C@@H](C2C=CC(N(C)C)=CC=2)[C@H](COC2C=CC=C(C(F)(F)F)C=2)C1)CCC>CN(C=O)C>[ClH:21].[CH3:18][N:17]([CH3:19])[C:14]1[CH:15]=[CH:16][C:11]([C@@H:8]2[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:35])[CH2:3][CH3:4])[CH2:6][C@H:7]2[CH2:20][O:33][C:30]2[CH:31]=[CH:32][C:26]3[O:25][CH2:24][O:28][C:27]=3[CH:29]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2cccc(C(F)(F)F)c2)C1
Reactant: CCCCN1CCC(c2ccc(N(C)C)cc2)C(CCl)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)CN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc3c(c2)OCO3)C1

Procedure:
Was prepared from the crude 1-(2-methylbutyl)-analogue of (18) (3.8 g), NaH (0.81 g) and sesamol (2.13 g) in DMF (50 ml) as described for compound (17). The crude product was purified several times on a silica gel column using ethylacetate and heptane/ether 4/1 as eluents. Compound (19) was identified by 1H NMR and MS. M.p. 238.5°-239.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:24])[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Cl:23].Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:11][O:12][C:13](=[O:24])[CH2:14][C:15]1[C:16]([Cl:23])=[CH:17][C:18]([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][C:20]=1[Cl:21]
Reactant: COC(=O)Cc1c(Cl)cc(N)cc1Cl
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Cc1c(Cl)cc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 46.5 h

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (5.0 g, 31.4 mmol), (4-amino-2,6-dichloro-phenyl)-acetic acid methyl ester (7.8 g 33.3 mmol), and a 4 N solution of HCl in dioxane (12 mL, 48.0 mmol, 2.9 equiv) in MeOH/dioxane (60 mL; 1:1, v/v) is stirred for 46.5 h at 100° C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (Hexane/EtOAc, 4:1), followed by trituration in diethyl ether, provides the title compound: ES-MS: 355.9/357.9 [M+H]+; tR=5.33 min (System 1); Rf=0.25 (Hexane/EtOAc, 4:1).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)=O.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(#N)C>[C:27]([O:26][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:23][CH2:22]1)=[O:31])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC#N
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(CCNC(=O)OCc2ccccc2)CC1
Yield: 77.5 %

Procedure:
Into a solution of 2-bromoethylamine hydrobromide (5.0 g) and potassium carbonate (5.06 g) in THF/water (20/5 ml) was added at 0° C. benzyl chloroformate (4.16 g), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to obtain benzyl 2-bromoethylcarbamate (7.32 g). A solution of benzyl 2-bromoethylcarbamate (7.23 g), tert-butyl 4-piperidinyl-carbamate formic acid salt (4.63 g) and triethylamine (8 ml) in acetonitrile (30 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate/hexane) to obtain benzyl 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]ethylcarbamate (5.5 g) as colorless crystals.