Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[C:12]([CH2:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2.O.O.[OH-].[Li+]>CO>[CH3:29][N:2]([CH3:1])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([CH2:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2
Reactant: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)O)C(=O)OC2

Procedure:
To a solution of 0.3 g (0.74 mmol) of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 7.4 ml of 4:1 methanol:water is added 0.13 g (2.96 mmol) of lithium hydroxide monohydrate. The solution is heated at 50°-60° C. for 4 hours. Upon cooling, the reaction is partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated to give (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)C(F)(F)F
Temperature: 118 °C
Yield: 42.1 %

Procedure:
In a manner similar to Example 6, ethyl trifluoroacetate (102 g, 0.72 m) was reacted with cyclohexylamine (70 g, 0.7 m). By-products/unreacted material were removed by heating the reaction mixture under increasing vacuum (final pressure 3 mm Hg) to 118° C. The pot residue was then recrystallized from hot ethyl acetate (~60 g) plus hexanes (~100 g) to yield 58 g solid which melted at 93°-95° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[F:20][C:21]([Si](C)(C)C)([F:23])[F:22].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)([OH:8])[C:21]([F:23])([F:22])[F:20])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
To a solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl) carbonyl]cyclohexane-carboxylate (608 mg, 1.756 mmol) in THF (15 ml) was added trifluoromethyl trimethylsilane (0.520 ml, 3.51 mmol). Then, tetrabutylammonium fluoride (7.0 ml, 7.00 mmol) was added to the mixture slowly. After 1 h, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexane) to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd. for C14H17BrF3NO3S [M+H]+ 416, 418. found 416, 418. 1H NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 4.11 (q, J=7.1, 2H), 2.47-2.32 (m, 1H), 2.28-1.92 (m, 4H), 1.55-1.16 (m, 5H), 0.90 (t, J=7.3, 3H).
Reaction SMILES: [ClH:1].CCOC(C)=O.[N:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1.[H][H]>[Pt]=O.C(O)C>[ClH:1].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/c2ccncc2)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC2CCNCC2)CC1

Procedure:
A 4 M hydrogen chloride/EtOAc solution (0.88 ml) and platinum oxide (100 mg) were added to an ethanol (25 ml) solution of tert-butyl 4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.02 g), followed by stirring in the presence of hydrogen (3.5 atm) for 24 hours. This was purged with argon, diluted with methanol, filtered through Celite, and concentrated under reduced pressure. The solid precipitated was washed with EtOAc/hexane, and dried under reduced pressure to obtain tert-butyl 4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (850 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](OC(ON=C(C#N)C(N)=O)=O)[CH3:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:23]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:24]
Reactant: CCOC(=O)ON=C(C#N)C(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 103.6 %

Procedure:
To a suspension of N-benzyloxycarbonyl-L-phenylalanine (1.5 g) and 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (0.95 g) in ethyl acetate (20 ml), a solution of triethylamine (0.7 ml) in ethyl acetate (5 ml) is dropwise added at -10°C, and the resulting mixture is stirred at the same temperature for 20 minutes and then at room temperature for 2 hours. After allowed to stand over night, the reaction mixture is treated as in Example A to give N-benzyloxycarbonyl-L-phenylalanine ethyl ester (1.7 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:27])([F:26])[F:1])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:23])[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Product: O=C(c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2)N1CCOCC1

Procedure:
Following the procedure for 109, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and morpholine gave 123. MS: (ESI+)=449.1. 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.6 Hz, 2H), 7.40 (dt, J=21.4, 10.7 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 5.89 (q, J=8.8 Hz, 2H), 4.57 (s, 4H), 3.61 (s, 4H), 3.52 (s, 4H)
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1)[CH2:2][CH3:3].[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.[OH-].[Na+]>ClCCl>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][CH:4]2[CH2:1][CH2:2][CH3:3])=[O:21])[CH:15]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: CCCC1Cc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCC1Cc2ccccc2N1C(=O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.76 g (4.7 mmol) 2-propyl-2,3-dihydro-1H-indole in 15 mL dichloromethane was added to 0.88 g (5.0 mmol) 6-chloro-pyrimidine-4-carboxylic acid chloride in 15 mL dichloromethane at 0° C. and then 4.7 mL (4.7 mmol) of a 1M sodium hydroxide solution were added dropwise. The reaction mixture was stirred for 30 min at 0° C. and then for 1 h at RT. The organic phase was separated off and evaporated down. The residue was purified on silica gel.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22](OC)=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>>[NH2:32][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16][CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][O:30][CH2:29]1
Reactant: NCC1(N)COC1
Reactant: COc1ccc2c(c1)SCCN(c1cc(Cl)c3cc(C)ccc3n1)C2
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) and 3-aminomethyl-oxetan-3-ylamine. MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (s, 1 H), 7.74-7.67 (t, 2 H), 7.61 (d, J=8.4 Hz, 1 H), 7.55 (d, J=7.6 Hz, 1 H), 7.32 (t, 1 H), 7.26 (t, 1 H), 6.27 (s, 1 H), 5.19 (s, 2 H), 4.77-4.70 (m, 4 H), 4.35 (s, 2 H), 4.12 (s, 2 H), 3.16 (t, J=9.6 Hz, 2 H), 2.49 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@@H:10]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (4R)-1-(tert-butyloxycarbonyl)-4-hydroxy-L-proline tert-butyl ester (573 mg, 1.99 mmol) in pyridine (3.5 mL) cooled to 0° C. was added methanesulfonyl chloride (0.31 mL, 3.99 mmol). The reaction mixture was stirred for 2 hours at ice temperature, diluted with ethyl acetate (30 mL), washed with 1M sodium hydrogencarbonate solution, 1M citric acid, water, dried (Na2SO4), and evaporated. The crude product was purified by flash silica gel chromatography eluting with 1% methanol/dichloromethane; yield 686 mg (94%). 400 MHz 1H NMR (CDCl3): δ1.42-1.44 (2s, 18H); 2.20 (m, 1H); 2.60 (m, 1H); 3.02 (s, 3H); 3.68-3.86 (m, 2H); 4.29 (m, 1H); 5.22 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[S:12])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:12][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Reactant: CCOC(CBr)OCC
Product: CCOC(=O)c1nc(SCC(OCC)OCC)[nH]c1C

Procedure:
prepared by reaction of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester with bromoacetaldehyde diethyl acetal. LC-MS: tR=0.70 min; [M+H]+=303.4.
Reaction SMILES: [Li].[CH3:2]C(NC(C)C)C.[F:9][CH:10]([F:27])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][C:13]=1[O:21][CH:22]1[CH2:26][CH2:25][O:24][CH2:23]1.[I-]>C1COCC1>[F:27][CH:10]([F:9])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:2])[C:19]#[N:20])=[CH:14][C:13]=1[O:21][CH:22]1[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: CC(C)NC(C)C
Reactant: N#CCc1ccc(OC(F)F)c(OC2CCOC2)c1
Agent: [I-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
N-(1-methylethyl)-2-propanamine lithium salt (0.0325 mol; 1 M in THF) was added dropwise and under N2 flow to intermediate 4 (0.0309 mol) in THF (70 ml), cooled to -78° C. The mixture was stirred for 30 minutes at -78° C. lodomethane iodide (0.034 mol) was added dropwise and the reaction mixture was stirred for 2 hours at RT. The mixture was quenched with a saturated aqueous NH4Cl solution, and extracted with ethylacetate. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl2), then by HPLC over silica gel (eluent: hexane/ethylacetate 3/2). The pure fractions were collected and the solvent, yielding 4.64 g (53%) of (±)-4-(difluoromethoxy)-alpha-methyl-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile (intermediate 9).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CN(c2ccc(-c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 110 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.45 mmol), phenylboronic acid (180 mg, 0.83 mmol), Pd(PPh3)4 (100 mg, 20 mol %) and aqueous Na2CO3 (0.83 mL of a 2M solution) in DME (3 mL) is placed in a microwave vial and heated at 110° C. for 15 min. The mixture is filtered, diluted with EtOAc and washed with 1N HCl. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[C:10]([O:14][C:15](=[O:30])[N:16]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:30])[N:16]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1
Reactant: FCc1cccc(Br)n1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1cccc(CF)n1)c1ccc(F)cc1
Yield: 78.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.95 mmol, Example 190(E)) and (4-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (276 mg, 0.95 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 300 mg (0.75 mmol, 79%) of [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1([CH2:26][OH:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:12][C:13]1([CH2:26][O:27][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
p-Toluenesulfonyl chloride (230 mg, 1.209 mmol) was added portionwise to tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (188 mg, 0.806 mmol), triethylamine (227 μL, 1.612 mmol), and DMAP (9.85 mg, 0.081 mmol) in dichloromethane (2015 μL) at 0° C. The solution was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic layer was washed with 0.2M HCl and then dried (MgSO4) and concentrated. The residue was dissolved in dichloromethane and loaded onto a 25+M Biotage silica column. Chromatography, eluting with a gradient of EtOAc in hexanes, gave tert-butyl 4-fluoro-4-(tosyloxymethyl)piperidine-1-carboxylate (251 mg, 0.648 mmol, 80%) as a clear semi-solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:40]1([C:46](=[O:48])[CH3:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:43]3[CH2:44][CH2:45][N:40]([C:46](=[O:48])[CH3:47])[CH2:41][CH2:42]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Yield: 44.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-piperazin-1-yl-ethanone hydrochloride (90 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-acetyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 17a (80 mg, yield 45%) as a white solid.
Reaction SMILES: [C:1](=[O:20])([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:2][CH:3](Cl)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([NH:24][C:25]1[C:26]([I:41])=[C:27]([N:36]([C:38](=[O:40])[CH3:39])[CH3:37])[C:28]([I:35])=[C:29]([C:32]([O-:34])=[O:33])[C:30]=1[I:31])(=[O:23])[CH3:22].[K+].[I-].[Na+]>CN(C=O)C>[C:21]([NH:24][C:25]1[C:26]([I:41])=[C:27]([N:36]([C:38](=[O:40])[CH3:39])[CH3:37])[C:28]([I:35])=[C:29]([C:32]([O:34][CH:3]([O:2][C:1]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:33])[C:30]=1[I:31])(=[O:23])[CH3:22]
Reactant: O=C(Oc1ccccc1)OC(Cl)CCc1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(CCc2ccccc2)OC(=O)Oc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-Chloro-3-phenylpropyl phenyl carbonate (0.30 g, 1.03 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methyl-amino)-2,4,6-triiodobenzenecarboxylate (0.62 g, 0.93 mmol) and sodium iodide (0.014 g, 0.093 mmol) in dry DMF (5 ml). After stirring at 50° C. for 5 hours and at room temperature for 2 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (15 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.26 g. Purity by HPLC: 94.4% 1H-NMR (DMSO-d6): delta=1.68 (NCH3COCH3); 2.06 (NHCOCH3); 2.38 (CH2CH); 2.83 (CH2CH2CH); 2.98 (NCH3); 7.02 (CH); 7.19-7.52 (phenyl); 10.15 ppm (NH). FAB/MS: 883 ((M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18]([S:21]([NH:24][NH2:25])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(O)C>[C:15]1([CH3:26])[CH:16]=[CH:17][C:18]([S:21]([NH:24][N:25]=[C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN=C(c2ccccc2)c2ccccc2)cc1

Procedure:
Benzophenone (15.0 parts, 0.082M ex Fluka) was stirred at reflux with p-toluene sulphonylhydrazine (15.33 parts, 0.082M ex Aldrich) in ethanol (125 ml) for 10 hours. Gradually a pale yellow solution formed from which the hydrazone gradually precipitated. After cooling to 20° C., diethylether (20 ml) was added and the hydrazone filtered and washed with ether. The hydrazone was obtained as a white powder (24.0 parts; 83% theory) mp 184°-6° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:6][CH:5]=1.Cl>CC(O)=O.O>[O:16]=[C:14]1[NH:13][C:12](=[O:17])[CH:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][CH:6]=2)[S:15]1
Reactant: COC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(C(=O)O)cc2)S1
Temperature: 120 °C
Yield: 41.5 %

Procedure:
A solution of methyl ester 351 (250 mg, 0.94 mmol) in AcOH (10 ml) was treated with conc. HCl (5 ml) and the reaction mixture was heated at 120° C. for 2 hrs, cooled and evaporated to produce a solid residue which was re-suspended in water and collected by filtration to afford the title compound (98 mg, 41% yield). LRMS: 251.3 (calcd.), 250.1 [M−H]− (found).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:33]3[CH2:34][CH2:35][N:36]4[C:41]([C:32]=3[NH:31][C:28]2=[CH:29][CH:30]=1)=[C:40]([CH2:42][CH3:43])[CH2:39][CH2:38][C:37]4=O>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:33]3[CH2:34][CH2:35][N:36]4[C:41]([C:32]=3[NH:31][C:28]2=[CH:29][CH:30]=1)=[C:40]([CH2:42][CH3:43])[CH2:39][CH2:38][C:37]4=[S:10]
Reactant: CCC1=C2c3[nH]c4ccc(OC)cc4c3CCN2C(=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCC1=C2c3[nH]c4ccc(OC)cc4c3CCN2C(=S)CC1
Yield: 60 %

Procedure:
Lawesson's reagent (0.5 nimol) is added portionwise, at 110° C., to a solution of 9-metlioxy-1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinoIizin-4-one (300 mg, 1.01 mmol) in anhydrous toluene (15 mL). After refluxing for 30 min. and evaporation of the toluene, the product is chromatographed on silica gel (99/1 chloroform/methanol eluent) and 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-alquinolizine-4-thione is thus recovered (60% yield).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[K+].O1CCCC1.Cl>O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:25][CH:26]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)[O-])cc3)no2)cc1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 50 °C

Procedure:
The pure potassium 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate obtained in Example 2, tetrahydrofuran (131 L) and water (131 L) were put into a 1000 L glass-lined reaction chamber, heated to 45 to 55° C., and 1N hydrochloric acid (82 L) was added to this reaction mixture for 20 or more minutes. Furthermore, water (607 L) was added to the reaction mixture for 30 or more minutes at the same temperature. This reaction mixture was cooled to 25 to 35° C. and its pH was adjusted to 3 or less with 6N hydrochloric acid. The product was isolated by a centrifugal separator and washed with water (164 L) and acetone (82 L) and dried by a vacuum drier to obtain pure 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (14.9 kg).