Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NS(C)(=O)=O)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 4, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with methanesulfonyl chloride gave the title compound as a colorless solid. MS: 386.5 (M+H+).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[C:13](=[O:22])[C:14]4[CH:15]=[N:16][N:17]=[CH:18][C:19]=4[C:20](=[O:21])[C:11]=3[N:10]=[N:9]2)=CC=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2[C:13](=[O:22])[C:14]3[CH:15]=[N:16][N:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:11]=2[N:10]=[N:9]1
Reactant: COc1ccc(Cn2nnc3c2C(=O)c2cnncc2C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cnncc2C(=O)c2[nH]nnc21

Procedure:
In the step (c), 1-(4-methoxybenzyl)-1H-[1,2,3]triazolo[4,5-g]phthalazin-4,9-dione prepared in the step (b) is dissolved in TFA and then refluxed for 40–50 hours. NaOH is added in remnants and washed with ethyl acetate, and then 1H-[1,2,3]triazolo[4,5-g]phthalazin-4,9-dione is obtained by acidifying the resulting aqueous layer to pH 1. Examples of halogenated alkylating agents include, but are not limited to, methyl iodide, ethyl iodide, propyl iodide and butyl iodide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[C:9]=1[C:29](OCC)=[O:30]>>[OH:7][C:8]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[C:9]=1[C:29]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:30]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(-c2cccs2)c(-c2ccccc2)c1O
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc(-c2cccs2)c(-c2ccccc2)c1O
Yield: 73.9 %

Procedure:
Using the procedure of Example 5, 10 g of amino thiazol and 6.9 g of the product of Step D were reacted to obtain 5.8 g of the expected product which was crystallized from acetonitrile melting at 260°-262° C.
Reaction SMILES: ClCCl.[CH:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO[CH:14]=[CH:15][C:16]([O:18][Si](C)(C)C)=[CH2:17]>FC(F)(F)C(O)=O.N1C=CC=CC=1.O>[C:5]1([CH:4]2[CH2:17][C:16](=[O:18])[CH:15]=[CH:14][O:11]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: C=C(C=COC)O[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1C=COC(c2ccccc2)C1
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a round flask of 5 ml having a magnet stirrer put therein, 19.1 mg (0.01 mmol) of the catalyst (tetrahydrate) obtained in Example 8 and 1 ml of dichloromethane were added for dissolution, then benzaldehyde (10 μl, 0.1 mmol) and 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (purity: 90%, 30.0 μl, 0.150 mmol) were added thereto, and the reaction was carried out at room temperature for 24 hours. After the reaction had been completed, two drops of trifluoroacetic acid was added by a microsyringe, three drops of pyridine was added by a microsyringe, and 1 ml of water was added. Successively, extraction with dichloromethane, drying over anhydrous magnesium sulfate, concentration and purification by preparative silica gel column chromatography (hexane/ethyl acetate=4/1) were carried out to obtain 16.1 mg of the desired compound (R)-2-phenyl-2,3-dihydro-4H-pyran-4-one. As a result of analysis, the yield was 93% and the optical purity was 19% (R).
Reaction SMILES: C(OC(COC1C=CC(F)=CC=1)/C=C/CNS(C)(=O)=O)(=O)C.C(OC(COC1C=CC(F)=CC=1)CCCNS(C)(=O)=O)(=O)C.BrCCCCCCC(OCC)=O.BrCC#CCCCC(OCC)=O.C([O:72][CH:73]([CH2:93][O:94][C:95]1[CH:100]=[CH:99][C:98]([F:101])=[CH:97][CH:96]=1)/[CH:74]=[CH:75]/[CH2:76][N:77]([CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][C:88]([O:90]CC)=[O:89])[S:78]([CH3:81])(=[O:80])=[O:79])(=O)C>>[OH:72][CH:73]([CH2:93][O:94][C:95]1[CH:100]=[CH:99][C:98]([F:101])=[CH:97][CH:96]=1)/[CH:74]=[CH:75]/[CH2:76][N:77]([CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][C:88]([OH:90])=[O:89])[S:78]([CH3:81])(=[O:80])=[O:79]
Reactant: CCOC(=O)CCCCCCN(C/C=C/C(COc1ccc(F)cc1)OC(C)=O)S(C)(=O)=O
Agent: CC(=O)OC(/C=C/CNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CC(=O)OC(CCCNS(C)(=O)=O)COc1ccc(F)cc1
Agent: CCOC(=O)CCCC#CCBr
Product: CS(=O)(=O)N(C/C=C/C(O)COc1ccc(F)cc1)CCCCCCC(=O)O

Procedure:
This compound is prepared by the procedure described in Example 2, Step I, except that N-[4-acetoxy-5-(4-fluorophenoxy)trans-2-pentenyl]methanesulfonamide is substituted for the N-[4-acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamide and ethyl 7-bromoheptanoate is substituted for ethyl 7-bromo-5-heptynoate. The product is thus ethyl 7-{N-[4-acetoxy-5-(4-fluorophenoxy)trans-2-pentenyl]methanesulfonamido}heptanoate. The subsequent hydrolysis (Example 2, Step J) affords the subject compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.Cl.[NH2:51][C@:52]1([C:62]([O:64][CH3:65])=[O:63])[CH2:54][C@@H:53]1[C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1>CN(C=O)C>[Br:61][C:58]1[CH:57]=[CH:56][C:55]([C@H:53]2[CH2:54][C@:52]2([NH:51][C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@]1(N)C[C@@H]1c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@]1(NC(=O)[C@@H]2CCCCN2C(=O)OC(C)(C)C)C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (9.05 mg) in DMF (3 mL) was added Hunig's Base (0.019 mL) followed by HATU (15 mg). The mixture was allowed to stir at room temp for 10 min. To this solution was added in one portion (1R,2R)-methyl 1-amino-2-(4-bromophenyl)cyclopropanecarboxylate hydrochloride (11 mg) and the mixture was stirred overnight. The mixture was evaporated to dryness, the residue extracted into diethyl ether and washed well with water and brine, then dried over sodium sulfate. The sample was passed through a small silica plug/eluting with diethyl ether to give (S)-tert-butyl 2-((1R,2R)-2-(4-bromophenyl)-1-(methoxycarbonyl)cyclopropylcarbamoyl)piperidine-1-carboxylate (6 mg) as a colourless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]([C:10]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)=CCOc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1coc2ccccc12
Temperature: 100 °C
Yield: 52 %

Procedure:
A solution of 1-iodo-2-(3-methylbut-2-enyloxy)benzene (5 g, 17.3 mmol) in propionitrile (10 mL) and diisopropylethylamine (9 mL, 52 mmol) is degassed with argon for 15 min. To this solution is added palladium acetate (423 mg, 1.73 mmol) and the reaction is heated to 100° C. overnight. The reaction is then cooled to room temperature and passed through a pad of celite, washing the filter cake with ethyl acetate (50 mL). The ethyl acetate and amine base are then removed under vacuum. The crude reaction mixture is then chromatographed using 100% hexanes to yield title compound as a colorless oil in 52% yield (1.3 g): 1H NMR (300 MHz, CDCl3) δ 7.7 (s, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.32-7.24 (m, 2H), 3.11-3.07 (m, 1H), 1.32 (2s, 6H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH2:33]([O:35][C:36]1[CH:37]=[C:38]([CH:66]=[C:67]([O:69][CH2:70][CH3:71])[CH:68]=1)[C:39]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:56]=[C:55]3[C:51]([CH2:52][N:53]([C@@H:58]([CH:63]([CH3:65])[CH3:64])[C:59]([O:61]C)=[O:60])[C:54]3=[O:57])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)=[O:40])[CH3:34]>>[CH2:33]([O:35][C:36]1[CH:37]=[C:38]([CH:66]=[C:67]([O:69][CH2:70][CH3:71])[CH:68]=1)[C:39]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:56]=[C:55]3[C:51]([CH2:52][N:53]([C@@H:58]([CH:63]([CH3:64])[CH3:65])[C:59]([OH:61])=[O:60])[C:54]3=[O:57])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)=[O:40])[CH3:34]
Reactant: CCOc1cc(OCC)cc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)c1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCOc1cc(OCC)cc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c1
Yield: 82 %

Procedure:
The compound of example 146 was prepared analogous to compound of example 98 by hydrolysis of compound of example 145.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]1=[O:10].NC1C=CC=CN=1.N([O-])=O.[K+].S(=O)(=O)(O)O.N1C=CC=CC1=O>>[Cl:9][C:4]1[C:3](=[O:10])[NH:2][CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Cn1cc(Cl)cc(Cl)c1=O
Agent: Nc1ccccn1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Product: O=c1[nH]cc(Cl)cc1Cl

Procedure:
The production of 2,3,5-trichloropyridine by reaction of N-methyl-3,5-dichloro-2-pyridone with phosgene as solvent is known. The process comprises introducing N-methyl-3,5-dichloro-2-pyridone into a toluene solution of phosgene, and heating the mixture in a closed system for 3 hours at 150° C. 2,3,5-Trichloropyridine is obtained in this manner in a yield of about 90% of theory (Ann. Chem. 486, 78-79 (1931)). The N-methyl-3,5-dichloro-2-pyridone required as starting material for carrying out this process is obtainable by reaction of 2-aminopyridine with potassium nitrite in a sulfuric acid solution to 2-pyridone (Arch. Pharm. 240, 250 (1903)), chlorination of this to give 3,5-dichloro-2-pyridone (J. Org. Chem. 23, 1614 (1958)), and subsequent methylation thereof (Ann. Chem. 486, 74 (1931).
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:15][C:14]([CH3:17])([CH3:16])[C@H:13]([OH:18])[CH2:12]2)=[N:4][C:5]([CH3:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:39]=[O:40])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:9][NH:8][C:7]2[C:2]([F:1])=[C:3]([N:11]3[CH2:12][C@@H:13]([OH:18])[C:14]([CH3:16])([CH3:17])[CH2:15]3)[N:4]=[C:5]([CH3:10])[N:6]=2)=[O:27])[CH2:29][N:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[O:40])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1nc(NN)c(F)c(N2C[C@@H](O)C(C)(C)C2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2C[C@@H](O)C(C)(C)C2)n1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (3S)-1-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-4,4-dimethyl-3-pyrrolidinol (0.125 g, 0.490 mmol) in DMF (3 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.1246 g, 0.408 mmol), N-methylmorpholine (0.225 ml, 2.046 mmol), 1-hydroxy-7-azabenzotriazole (67 mg, 0.492 mmol), and EDC (94 mg, 0.490 mmol). The mixture was stirred overnight and then purified directly by Gilson RPLC to give [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(4S)-4-hydroxy-3,3-dimethyl-1-pyrrolidinyl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1606 g, 73% yield) as a purple oil. LCMS: (M+H)+: 543.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]([CH3:25])[C:8](=[O:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([O:22][CH3:23])=[CH:11][CH:10]=2.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[OH:1][CH2:2][CH2:3][S:4]([CH2:5][C:6]1[N:7]([CH3:25])[C:8](=[O:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:13][C:12]([O:22][CH3:23])=[CH:11][CH:10]=2)=[O:34]
Reactant: COc1ccc2c(=O)n(C)c(CSCCO)c(-c3ccccc3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(CS(=O)CCO)c(-c3ccccc3)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-{[(2-hydroxyethyl)thio]methyl}-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (31 mg, 0.087 mmol) in 2 mL of dichloromethane was added at 0° C. meta-chloroperbenzoic acid (16 mg, 0.091 mmol). After 15 minutes, the reaction mixture was partitioned between EtOAc and 2M Na2S2O3 solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. 1H-NMR (500 MHz, CDCl3) δ 8.43 (d, J=9.0 Hz, 1H), 7.44-7.55 (m, 3H), 7.33 (br d, J=8 Hz, 2H), 7.06 (dd, J=8.8, 2.4 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 4.28 (d, J=13.9 Hz, 1H), 3.98 (d, J=13.9 Hz, 1H), 3.96-4.04 (m, 2H), 3.84, (s, 3H), 3.68 (s, 3H), 2.85 (m, 1H), 2.70 (m, 1H), ppm. ESI+ MS: 372.19 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([N:14]1[C:26]2[CH2:25][N:24]([CH3:27])[CH2:23][CH2:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=2)#[CH:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[CH3:27][N:24]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]([C:12]#[C:13][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[C:26]=2[CH2:25]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CCN(C)C2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(S(N)(=O)=O)cc2)CN(C)CC1

Procedure:
A mixture of 4-bromo-benzenesulfonamide (200 mg, 0.84 mmol), 9-ethynyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (228 mg, 1.01 mmol), TBAF.3H2O (801 mg, 2.54 mmol) and dichloro bis(triphenylphosphine) palladium(II) (30 mg, 0.042 mmol) was stirred at 85° C. for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×30 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by reverse phase HPLC to yield 4-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-ylethynyl)-benzenesulfonamide. 1H NMR (CDCl3, freebase) δ (ppm): 7.9 (d, 2H), 7.6 (d, 2H), 7.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 3.78 (s, 2H), 2.82 (t, 2H), 2.79 (t, 2H), 2.6 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[NH:23][C:22]2=[O:31]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[NH:23][C:22]2=[O:31]
Reactant: O=C1NC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: O=C1NC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 7-chlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1 tR=1.73, min, m/z=437
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:10]([NH:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: NOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(CNOCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
A mixture of 4 g of O-benzylhydroxylamine, 4.28 g of benzyl bromide, and 12 g of K2CO3 in 50 ml of ethanol was stirred at 50° C. overnight. After removal of organic solvent, water was added to the residue and the mixture was then extracted with ethyl acetate. The combined extracts were dried and evaporated to give 4 g of crude product. Purification by dry column chromatography gave 1.8 g of oily product.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:35])[O:21][CH2:22][C:23]1([CH2:27][S:28][C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:13]=[C:3]([NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:2]([C@@H:14]([NH:19][C:20](=[O:35])[O:21][CH2:22][C:23]1([CH2:27][S:28][C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:24][CH2:25][CH2:26]1)[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1]
Reactant: CCCC[C@H](NC(=O)OCC1(CSc2ncccn2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OCC1(CSc2ncccn2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
To a solution of 0.135 g (0.27 mmol) of {1-[(2-pyrimidinylsulfanyl)methyl]cyclobutyl}methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate in 2.0 mL of dichloromethane was added 0.031 g (0.375 mmol) of sodium bicarbonate followed by the addition of 0.137 g (0.32 mmol) of Dess-Martin periodinane. The reaction was stirred for 15 min and poured directly onto a silica gel column eluting with ethyl acetate:hexane (3:7) as the eluent to afford 0.094 g (70%) of {1-[(2-pyrimidinylsulfanyl)methyl]cyclobutyl}methyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=5 Hz, 2H), 7.31-7.08 (m, 6H), 6.88 (t, J=5 Hz, 1H), 5.25 (d, J=7 Hz, 1H), 4.89-5.20 (m, 2H), 4.08 (s, 2H), 3.43 (s, 2H), 2.03-1.80 (m, 6H), 1.79-1.42 (m, 5H), 1.41-1.25 (m, 4H), 0.81 (br s, 3H). LC-MS m/z 499 (M+H).
Reaction SMILES: [C:1]1([N:7]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:8][CH:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:20]3)=[O:16])[C:10]([O:12]C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[CH3:33][NH:32][C:28]1[N:27]=[C:26]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:15]([NH:14][CH:9]([CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:10]([OH:12])=[O:11])=[O:16])=[CH:25][CH:24]=3)[CH:31]=[CH:30][N:29]=1
Reactant: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)OC)ccc3[nH]2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)O)ccc3[nH]2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.4 %

Procedure:
4.0 g of the methyl ester 46 were dissolved in 400 ml of methanol, 40 ml of a 2N aqueous solution of NaOH were added and the whole was stirred at room temperature for 12 h. After the solvents had been evaporated, the residue was dissolved with water and the pH was adjusted to ˜5 using a saturated solution of NaH2PO4. The resulting precipitate was filtered off and washed with water. This resulted in 1.3 g (yield 93%) of the acid 48.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:22][CH3:23])[C:12]([O:14]CC3C=CC=CC=3)=[CH:13][C:7]=2[C:6]=1[Cl:24])=[O:4].Cl>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:22][CH3:23])[C:12]([OH:14])=[CH:13][C:7]=2[C:6]=1[Cl:24])=[O:4]
Reactant: COC(=O)c1sc2cc(OC)c(OCc3ccccc3)cc2c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1sc2cc(OC)c(O)cc2c1Cl

Procedure:
3-Chloro-5-benzyloxy-6-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.7 g), acetic acid (17.5 ml) and concentrated hydrochloride acid (2.1 ml) was refluxed for six hours. The mixture was cooled and evaporated to dryness. The resultant mixture was extracted first into diethyl ether and then into a solution of 1M sodium hydroxide. The water phase was acidified with 6M hydrochloric acid. The solution was stirred in cool for two hours and filtered. The solid was washed with water and dried under vacuum. The product was a mixture of two compounds and it was used for the next step without any purification.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>CCCCCC>[F:27][C:28]([F:37])([F:38])[O:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:20][CH2:19][C:6]3([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2

Procedure:
This material was prepared in analogy to example 1 step D) from 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, dimethylaluminium chloride in hexane and 4-trifluoromethoxy-phenylamine, with concomitant cleavage of the Boc protecting group at the reaction conditions applied. MS (ESI): 315.2 (MH+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14](OS(C)(=O)=O)[C@@H:15]1[CH2:19][C@@H:18]([CH2:20][CH3:21])[C:17](=[O:22])[O:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:15]1[O:16][C:17](=[O:22])[C@H:18]([CH2:20][CH3:21])[CH2:19]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 60 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
7.91 g of sodium azide (122 mmol) was added to a solution of 29.5 g of methanesulfonic acid (R)-2-benzyloxy-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl ester obtained in Example (106d) (86.3 mmol) in N,N′-dimethylpropyleneurea (300 ml) at room temperature, and the mixture was stirred at 60° C. for two days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1) to obtain 23.1 g of the title compound (yield: 93%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:12][C:13]1([CH:14]=[O:9])[CH2:22][CH2:21][C:16]2([CH2:17][CH2:18][CH2:19][O:20]2)[O:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=COC2(CCCO2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C=O)CCC2(CCCO2)O1
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
To a cooled and stirred solution of 8.80 g of 85% m-chloroperbenzoic acid in 120 ml of methylene chloride was added 6.16 g of 8-methyl-1,6-dioxaspiro[4.5]dec-7-ene in 20 ml of methylene chloride. The exothermic reaction was kept below 15° C. After 15 minutes, the mixture was poured into 600 ml of saturated potassium carbonate. The resulting organic layer was then washed with aqueous base, dried and distilled to yield 4.37 g of the desired product as a colorless liquid, b.p. 65°-70° C. (1 torr.).