Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][CH:32]1[C:37](=[O:38])[NH:22][CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[CH:13][N:12]([S:2]([C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=3)(=[O:3])=[O:4])[C:16]2=[N:17][CH:18]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CN(C(=O)OC(C)(C)C)CCC4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (29.6 g, 87.0 mmol, Step F), 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (21.2 g, 87.0 mmol, Step G) and HATU (33.2 g, 87.0 mmol) in DCM (400 mL) was added DIEA (46.0 mL, 263 mmol). After stirring for about 18 h at ambient temperature, the reaction mixture was washed with aqueous saturated NaHCO3 (400 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (330 g column) eluting with a gradient of 50-100% EtOAc in heptane to give tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 95%) as a tan foam: LC/MS (Table 2, Method a) Rt=2.38 min; MS m/z: 528 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:39][NH2:40]>CCO>[NH2:5][C:4]1[C:3]2[C:2](=[N:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([N:23]5[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[NH:25][C:24]5=[O:32])[CH2:19][CH2:18]4)=[CH:14][CH:15]=3)=[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:6]=2)[NH:40][N:39]=1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2nc(-c3ccc(CN4CCC(n5c(=O)[nH]c6ccccc65)CC4)cc3)c(-c3ccccc3)cc12

Procedure:
The solution of 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (1-6; 0.040 g, 0.077 mmol) and hydrazine (0.2 mL) in EtOH (2 mL) was heated to 130° C. in microwave for 10 min. The mixture was concentrated, treated with aqueous Na2CO3 solution (5 mL, 2 M) and extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 1-{1-[4-(3-amino-5-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (1-7). 1H-NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 8.71 (s, 1H), 7.95 (s, 1H), 7.35 (d, J=8.1, 2H), 7.18-7.27 (m, 8H), 6.98-7.05 (m, 2H), 6.85 (d, J=7.5, 1H), 4.33-4.36 (m, 1H), 4.21 (s, 2H), 3.55 (s, 2H), 3.00-3.02 (m, 2H), 2.41-2.47 (m, 2H), 2.13-2.17 (m, 2H), 1.77-1.79 (m, 2H). LRMS m/z (M+H) Calcd: 516.5, found: 516.2.
Reaction SMILES: C([Mg]Cl)(C)(C)C.[F:7][C:8]1[C:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([CH2:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[C:16]([F:30])[C:15]=2[F:31])=[C:12]([F:32])[C:11]([F:33])=[C:10]([F:34])[C:9]=1[F:35].[F:36][C:37]([F:48])([F:47])[S:38]([O:40]S(C(F)(F)F)=O)=[O:39].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O.Cl>O.C(OCC)C>[F:32][C:12]1[C:13]([C:14]2[C:15]([F:31])=[C:16]([F:30])[C:17]([CH:22]([S:38]([C:37]([F:48])([F:47])[F:36])(=[O:40])=[O:39])[S:23]([C:26]([F:27])([F:28])[F:29])(=[O:25])=[O:24])=[C:18]([F:21])[C:19]=2[F:20])=[C:8]([F:7])[C:9]([F:35])=[C:10]([F:34])[C:11]=1[F:33]
Reactant: O=S(OS(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)C(F)(F)F
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(C(c1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A tert-butyl magnesium chloride (5 mL, 10 mmol, 2.0 M diethylether solution) was added to a diethylether (120 mL) solution dissolved with {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}(triflyl)methane (4.6 g, 10 mmol), at −78° C. under argon atmosphere. After the reaction solution was stirred for 0.5 hour at −78° C., it was further stirred for 0.5 hour at 0° C. Then, the solution was cooled again to −78° C., trifluoromethane sulfinic acid anhydride (0.84 mL, 5 mmol) was added, and the resultant solution was stirred for 2 hours at room temperature. Further, tert-butyl magnesium chloride (3.75 mL, 7.5 mmol, 2.0 M diethylether solution) was added at −78° C. After the reaction solution was stirred at −78° C. for 0.5 hour, it was stirred at 0° C. for 0.5 hour. The solution was cooled again to −78° C., trifluoromethanesulfonic acid anhydride (0.84 mL, 5 mmol) was added, and the resultant solution was stirred for 2 hours at room temperature. After the reaction was completed, water was added, further neutralized with 1 M hydrochloric acid water, and the water phase was washed with hexane. Then, said water phase was acidified with 4 M hydrochloric acid water, and extracted with diethylether. The organic phase was dried with magnesium sulfate, filtrated, and the solvent was removed under reduced pressure. The crude product was sublimated (8 to 9 Pa, 150° C., and the aimed {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane (2.79 g, 4.7 mmol, 47% yield) was isolated. 1H NMR (CDCl3, 300 MHz) δ 6.32 (s, 1H, CH), 19F NMR (CDCl3, 282 MHz) δ−75.1 (s, 6F, 2CF3), −127.72 to −127.58 (m, 1F), −133.43 (dt, J=10.2, 21.3 Hz, 1F), −134.60 (dt, J=9.4, 21.3 Hz, 1F), −137.08 to −137.35 (m, 2F), −140.07 (br, 1F), −148.38 (t, J=21.3 Hz, 1F), −160.01 (dt, J=6.2, 21.3 Hz, 2F).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:23]([O:25]CC)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:23]([OH:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Ethyl 3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,9,10-tetrahydro-4H-pyrimido[1,2-d][1,4]oxazepine-2-carboxylate (920 mg, 2.5 mmol) was dissolved in 5 mL of THF and to it was added with stirring LiOH (120 mg, 5 mmol) and 5 mL water. After 30 min, the THF was evaporated and the aqueous layer was acidified with dil HCl. This was extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. Trituration from Et2O gave the title compound (790 mg, 91%) as a solid: 1H NMR (300 MHz, CDCl3) δ: 1.40 (s, 6H), 3.60 (s, 2H), 3.65-3.95 (m, 2H), 4.10-4.90 (m, 2H), 5.41 (s, 2H), 7.25-7.42 (m, 3H), 7.45-7.58 (m, 2H). LC/MS (M+H): 345.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[CH2:8](CS([O-])(=O)=O)[CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH3:21])[CH3:16])[CH3:11]>>[CH2:8]([O:6][CH2:5][CH2:4][CH2:3][OH:7])[CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH:20]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:21])[CH3:16])[CH3:11]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCS(=O)(=O)[O-]
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOCCCO
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
Sodium hydride was added carefully to a solution of 1,3-propanediol (7.6 g, 100 mmol) in anhydrous N,N-DMF (30 mL). Phytanylmethanesulfonate (1.5 g, 4 mmol) was added and the mixture was heated to 60° C. and stirred for 4 h. The reaction mixture was then poured into ice/H2O, extracted with dichloromethane, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using 20% ethyl acetate/hexanes to give 3-(phytanyloxy)propan-1-ol (1.25 g, 87% yield)
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:21]=[CH:20][N:19]=[CH:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:26]([C:25]4[CH:24]=[CH:23][C:22]([N:17]5[CH:21]=[CH:20][N:19]=[CH:18]5)=[CH:29][CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(-n4ccnc4)cc3)nc(=O)c1-2
Temperature: 130 °C
Reaction time: 72 h
Yield: 94.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.18 g, 5.32 mmol), 4-(1-imidazolyl)benzaldehyde (1.37 g) and xylenes (8 ml) was warmed to 130° C. for 30 minutes, then to 160° C. for three days. The reaction mixture was cooled, and the product was collected by filtration and washed with Et2O to afford 1.88 g of 1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl)phenyl]pyrazolo [3,4-d]pyrimidin-4-one as the 6,7-saturated derivative. This derivative was mixed with ethanol (300 ml) and 30% H2O2 (3.0 ml) and refluxed overnight. Additional 30% H2O2 (3 ml) was added and the mixture was refluxed for 8 hours. An additional 10 ml of 30% H2 O2 was added and the mixture was refluxed overnight. Starting material was still present so an additional 10 ml of 30% H2O2 was added and the mixture was refluxed for 4 hours and then additional 30% H2O2 (10 ml) was added and the mixture was stirred for 1 hour, then was allowed to stand at room temperature overnight. The reaction mixture was stripped to a yellow liquid and purified by column chromatography on silica gel eluting with ethyl acetate (100%), then 5% methanol/ethyl acetate to afford 0.4 g of 1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl)phenyl]-pyrazolo-[3,4-d] pyrimidin-4-one 1/2 hydrate, m.p.>300° C.
Reaction SMILES: Cl.[O:2]=[C:3]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(Cl)Cl>[C:27]1([S:33]([N:24]2[CH2:23][CH2:22][N:21]([C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:20])[C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[CH2:26][CH2:25]2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCN(S(=O)(=O)c2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
TEA (0.074 mL, 0.53 mmol) was added dropwise to a chilled (0° C.) mixture of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) in DCM (5 mL). After 5 minutes, benzenesulfonyl chloride (0.032 mL, 0.26 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. DCM was added, followed by the addition of iced water. The product was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (using silica gel of mesh size of 60-120 and 70:30 EtOAc:hexane as eluent) to afford N-[2-(4-benzenesulfonyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide in 47% yield. LC-MS purity: 98%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.8 (m, 3H), 7.6 (m, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.1 (d, 2H), 7 (d, 2H), 4.1 (d, 2H), 3.6 (m, 4H), 2.9 (m, 4H).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24](OCC)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1.C[Al](C)C>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][C:22]([C:24]([N:39]3[CH2:38][CH2:37][N:36]([CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:41][CH2:40]3)=[O:25])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCN(C4CCN(C)CC4)CC3)o2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using Ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.07 mmol), 1-(1-methylpiperidin-4-yl)piperazine (26 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). A portion of the crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:20]=[N:21][C:22]=1[CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:20]=[N:21][C:22]([CH2:23][O:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1cnc(COCC(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1cnc(COCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 44 %

Procedure:
The title compound is prepared in 44% yield (240 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (370 mg, 1.3 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (450 mg, 1.3 mmol, Amine-65, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [N+](=C)=[N-].[CH3:4][S:5]([CH:8]([CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:7])=[O:6].[C:28](O)(=O)C>CCOCC>[CH3:4][S:5]([CH:8]([CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:28])=[O:16])(=[O:6])=[O:7]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCCC(CCCCCCC(=O)OC)S(C)(=O)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 8-methylsulfonyl-12-hydroxyheptadecanoic acid (10.8 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 8-methylsulfonyl-12-hydroxyheptadecanoate, a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4](C2CC3(CC(C(OC)=O)C3)C=2)[O:3]1.FC(F)(F)S(O[C:27]1[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH:28]=1)(=O)=O>>[CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH:28]=2)[O:3]1
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Reactant: CCOC(=O)CC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: CCOC(=O)CC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Yield: 99 %

Procedure:
The title compound was prepared following the method described in step 2 for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, using ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate as the reactant. (99% yield), MS: m/e 295.2 (M+H)+, 2.28 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.54 (d, J=2.3 Hz, 1H), 4.15 (q, J=7.3 Hz, 2H), 2.41-1.99 (m, 7H), 1.93-1.71 (m, 2H), 1.38-1.22 (m, 15H).
Reaction SMILES: C([O:8][C:9]1[C:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:10]=1[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[N:32]=[CH:31]2)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[OH:8][C:9]1[C:14]([NH:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:10]=1[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[N:32]=[CH:31]2
Reactant: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(OCc2ccccc2)c(-c2ccc3c(cnn3C)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(O)c(-c2ccc3c(cnn3C)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
A solution of Intermediate 56 (1.62 g) in a mixture of ethyl acetate (10 ml) and methanol (3 ml) was added with 10% palladium/carbon (29 mg), and stirred at room temperature for 17 hours under hydrogen atmosphere. The reaction mixture was filtered, and the solvent of the filtrate was evaporated under reduced pressure to obtain the title compound (Intermediate 57, 1.19 g).
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[CH2:14][S:13][C:12]([NH2:15])=[N:11]1.Cl>C(O)C.C(OCC)C>[ClH:1].[ClH:1].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][C@@H:10]1[CH2:14][S:13][C:12]([NH2:15])=[N:11]1
Reactant: NC1=NC(Cc2cnccn2)CS1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NC1=N[C@H](Cc2cnccn2)CS1
Yield: 25.6 %

Procedure:
A racemic mixture of 2.9 g of (4RS)-4-(2-pyrazinylmethyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is separated on a Chiralcel OD10μ column in a heptane/ethanol/triethylamine mixture (80/20/0.1 by volume). The fractions containing the expected product are concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue obtained is dissolved in 5 cm3 of ethanol, followed by addition of 6 cm3 of hydrochloric acid dissolved in diethyl ether and 15 cm3 of diethyl ether. After filtration, washing with 15 cm3 of diethyl ether and drying, 0.371 g of (+)-(4R)-4-(2-pyrazinyl-methyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is obtained in the form of a beige-coloured solid melting at 154° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.22 (d, J=6.5 Hz: 2H); 3.45 (dd, J=11.5 and 5.5 Hz: 1H); 3.75 (dd, J=11.5 and 8 Hz: 1H); 4.73 (mt: 1H); 8.60 (broad d, J=2.5 Hz: 1H); 8.63 (dd, J=2.5 and 1.5 Hz: 1H); 8.66 (broad s; 1H); 9.09 (unresolved complex: 1H); 9.58 (unresolved complex: 1H); 9.95 (broad s: 1H); (αD20=+46.3+/−1.1 at a concentration of 0.5% in methanol)].
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li]CCCC.Cl[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl>C1COCC1.CCCCCC>[C:1]12([O:11][C:12]3[CH:13]=[CH:14][C:15]([N:16]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:17][CH:18]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reactant: ClCCOCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1cc(N2CCOCC2)ccc1OC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
To 12.2 g (0.050 mole) of 4-(1-adamantyloxy)aniline dissolved in 200 ml of THF cooled in an ice bath was added dropwise with stirring 47 ml of a 1.07 M solution of n-BuLi in hexane. During the addition 100 ml of THF was added to the reaction mixture, and the mixture was stirred for one hour. 7.16 g (0.050 mole) of bis(2-chloroethyl)ether was added (as a solution in THF) and the mixture was refluxed for nineteen hours and allowed to cool. An additional 47 ml of the 1.07 M solution of n-BuLi in hexane was added dropwise with stirring to the reaction mixture cooled in an ice bath, and the mixture was stirred for one hour at room temperature and refluxed for twenty-three hours.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)NC(=O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reaction time: 4 h
Yield: 76.3 %

Procedure:
To a mixture of 6-amino-2-oxindole (1 g) and acetyl chloride (0.79 g) in 10 ml of dichloromethane at 0° C. was added triethylamine (1 g). The mixture was brought to room temperature and stirred for 4 hours protected from atmospheric moisture with a dry-tube. The solvent was then evaporated and the residue was recrystallized from methanol to give 0.98 g (77%) of 6-acetylamino-2-oxindole as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:15]3[CH2:14][CH2:17][N:16]3[C:7](=[O:9])[C:6]=2[CH:13]=1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CS(C)=O
Product: O=C1Nc2ccc(F)cc2C(=O)N2CC[C@@H]12

Procedure:
A mixture of 23.7 g (0.131 mol) of 5-fluoro-isatoic acid anhydride, 13.23 g (0.131 mol) of L-azetidine-2-carboxylic acid and 150 ml of dimethyl sulphoxide is heated to 90° for 3 hours, subsequently evaporated in a high vacuum and the residue is heated in a high vacuum for 17 hours. By recrystallization from methanol there is obtained (S)-6-fluoro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 216°-217°.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)(=O)C(C)(C)C.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:38]([O:46][CH2:47][CH3:48])(=[O:45])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([C:6](=[O:8])[CH:5]([O:4][C:3]1[CH:10]=[C:11]([Cl:15])[C:12]([Cl:14])=[CH:13][C:2]=1[Cl:1])[CH3:9])[C:38]([O:46][CH2:47][CH3:48])=[O:45])[CH3:44]
Reactant: CC(Oc1cc(Cl)c(Cl)cc1Cl)C(=O)O
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)C(=O)Cl
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 89.7 %

Procedure:
One proceeds in an analogous manner to Example 4 except that 27 g of 2-(2',4',5'-trichloro-phenoxy)-propionic acid are reacted first with 12 g of pivaloyl chloride and thereafter with diethyl-ethoxy-magnesium malonate prepared from 17.6 g of diethyl malonate. The reaction mixture is worked up. Thus 37 g of the desired compound are obtained in the form of pale yellow crystals, yield 91%, mp.: 62°-66° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[O:11][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: OCCc1ccc(O)c(F)c1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D120 starting from 2-fluoro-4-(2-hydroxyethyl)phenol and (3-(trifluoromethyl)phenyl)boronic acid.