Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1.[N+:15]([O-])([O-:17])=[O:16].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: O=[N+]([O-])c1c(Cl)cc(N2CCOCC2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
To a solution of 4-(4,6-dichloropyridin-2-yl)-morpholine (3.90 g) in concentrated sulfuric acid (40 mL) was added potassium nitrate (1.80 g) over 10 minutes. The reaction mixture was stirred for 16 hours at ambient temperature and then poured in to crushed ice (500 g). The reaction mixture was made alkaline with concentrated sodium hydroxide and extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to flash chromatography (SiO2, heptane/ethylacetate 3:1) to furnish 2.26 g (49% yield) of the title compound as a yellow solid. LC-MS (m/z) 278.0 (M+); tR=3.10, (UV, ELSD) 96.5%, 98.8%. 1H NMR (500 MHz, CDCl3): 3.62 (m, 4H), 3.80 (m, 4H), 6.50 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]2[CH2:15][CH2:16][C:17](=[CH2:18])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]2[CH2:15][CH2:16][C:17]3([CH2:18][CH:21]3[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C1CCc2cnc(OCc3ccccc3)cc21
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC12CCc1cnc(OCc3ccccc3)cc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
Compound H6.6 (50.0 mg, 211 μmol) and rhodium (ii) acetate, dimer (9.31 mg, 21.1 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) were mixed in 1.6 mL dry DCM. The resulting solution was refluxed at 45° C. for 10 minutes. Ethyl diazoacetate (26.2 μL, 253 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was then added to the mixture very slowly. After 1 hour, the reaction was cooled to room temperature. The catalyst was then filtered off, and the solvent was concentrated down with silica gel. The product was purified by column chromatography to give H6.7 (25.1 mg, 36.9%). NMR confirmed that the product was the trans isomer. MS ESI (pos.) m/e: 324.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.55-7.60 (3H, m), 7.37-7.47 (4H, m), 4.90 (2H, d, J=3.7 Hz), 4.12 (2H, q, J=7.1 Hz), 2.92 (2H, d, J=19.3 Hz), 2.82 (1H, dd, J=8.6, 6.4 Hz), 2.31 (1H, dd, J=8.4, 5.0 Hz), 2.19 (2H, ddd, J=8.7, 6.8, 2.8 Hz), 1.36 (1H, dd, J=6.0, 5.5 Hz), 1.21 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@H:5]([CH3:10])[C:6]([O:8]C)=[O:7].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CC(N(C)C)=O>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 95 °C
Reaction time: 19 h
Yield: 94.5 %

Procedure:
Methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (223 mg, 91% ee) was dissolved in DMAc (3 ml) and potassium carbonate (474.1 mg) was added thereto at room temperature. The liquid reaction mixture was stirred at 95° C. for 19 hours. After adding an aqueous solution of sodium hydroxide (3 mol/l), the liquid reaction mixture was stirred for 1 hour and then adjusted to pH 2 with hydrochloric acid (3 mol/l) followed by extraction with IPE. Next, it was dried over anhydrous magnesium sulfate. After evaporating the solvent, the crude product thus obtained was recrystallized from a solvent mixture of methylene chloride with normal hexane to thereby give the title compound (198 mg) as colorless crystals. The optical purity of this product was 0% ee. Various spectral data of this product was identical with those obtained in Example 23.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[NH:10][C:9](=O)[N:8]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(Cl)s2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-1H-pyrimidin-2-one (10.0 g, 35.6 mmol) and phosphoroxychloride (50 ml) according to the general procedure I. Obtained as a brown oil (10.4 g, 98%). MS (EI) 298.0, 299.9 [(M)+].
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].[H][H]>C(O)C.[Ni]>[CH2:20]([OH:21])[CH2:19][CH:17]([CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:18]
Reactant: [H][H]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Yield: 99.5 %

Procedure:
A solution of phytol (49.3 g, 166 mmol) in ethanol (250 ml) was reduced with hydrogen gas at atmospheric pressure over Raney nickel for 3 days. The catalyst was removed by filtration through Celite® and the filtrate concentrated under reduced pressure to give phytanol (49.3 g, 100%). 1H-n.m.r. (CDCl3) δ0.8-0.95 (m, 15H), 1.0-1.75 (m, 24H), 3.65-3.75 (m, 2H). 13C-n.m.r. (CDCl3) δ19.67 (3×Me), 22.60 (Me), 22.69 (Me), 24.36 (CH2), 24.45 (CH2), 24.78 (CH2), 27.95 (CH), 29.50 (CH), 32.76 (2×CH), 37.28-37.43 (m, 5×CH2), 39.35 (CH2), 39.73 and 40.05 (together CH2), 61.18 (CH2).
Reaction SMILES: O.[OH-].[Li+].[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][F:8]>O.C1COCC1>[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][F:8]
Reactant: COC(=O)c1cnc(Oc2cc(OC(CF)CF)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)cn3)cc(OC(CF)CF)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
Lithium hydroxide monohydrate (77 mg, 1.82 mmol) in water (2 mL) was added to methyl 5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate (325 mg, 0.73 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous residue washed with ethyl acetate to remove impurities then acidified with 1M citric acid. Ethyl acetate was added and a white solid removed by filtration and dried in vacuo to give the desired compound as a white solid (0.28 g). 1H NMR δ (d6-DMSO): 3.79 (s, 3H), 4.77 (m, 4H), 5.12 (t, 1H), 6.59 (s, 1H), 7.22 (s, 1H), 7.50 (s, 1H), 7.62 (s, 2H), 8.69 (s, 1H), 8.80 (s, 1H), 10.90 (s, 1H), 13.50 (s, 1H), m/z 434 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:26])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:15]C(OCC2C=CC=CC=2)=O)[CH2:4][N:3]1[S:27]([OH:30])(=[O:29])=[O:28].[K].[H][H].Cl>[Pd]>[NH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([NH:6][C@H:5]1[CH2:4][N:3]([S:27]([OH:30])(=[O:28])=[O:29])[C:2]1=[O:1])=[O:26]
Reactant: O=C(NCc1ccccc1C(=O)N[C@H]1CN(S(=O)(=O)O)C1=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [K]
Product: NCc1ccccc1C(=O)N[C@H]1CN(S(=O)(=O)O)C1=O

Procedure:
The deprotection of (S)-2-oxo-3-[[2-[[[(phenylmethoxy)carbonyl]amino]methyl]benzoyl]amino]-1-azetidinesulfonic acid, potassium salt (see example 167) using hydrogen gas, palladium on charcoal, and hydrochloric acid, yields the title compound, melting point 162°-165° C.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][C:24]([F:23])([F:34])[F:35])=[CH:27][CH:28]=5)[CH2:20][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCNC[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To (8S,9aS)-8-[(5-cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (50 mg, 0.154 mmol, Part D) in anhydrous dichloroethane (0.7 mL) was added 4-(trifluoromethoxy)benzaldehyde (38 mg, 0.2 mmol), and N-ethyl-N-isopropylpropan-2-amine (39.8 mg, 0.308 mmol). After 10 minutes, sodium triacetoxyborohydride (75 mg, 0.354 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate) to give 33 mg (46.4% yield) of the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 (m, 2H), 0.98 (m, 2H), 1.82 (m, 1H), 2.12 (m, 1H), 2.20-2.32 (m, 2H), 2.42 (dd, J=12, 8 Hz, 1H), 2.61 (m, 1H), 2.70-2.90 (m, 3H), 3.50 (br d, J=12 Hz, 1H), 3.57 (br d, J=12 Hz, 1H), 3.62-3.72 (m, 2H), 4.12 (m, 1H), 5.29 (m, 1H), 7.31 (d, J=9 Hz, 2H), 7.43 (d, J=9 Hz, 2H), 8.15 (s, 1H), 8.18 (s, 1H); MS (ESI) m/z 463.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]3)[CH:13]=[CH:12][N:11]=[CH:10]1.Cl.C([O-])(O)=O.[Na+]>N1CCCCC1.C(O)(=O)C>[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[C:22](=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:21][CH2:20]3)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccccn2)CCc2cc(OCCn3ccnc3)ccc21
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
2-Pyridine carboxaldehyde (0.202 g, 1.9 mmol) was added to a mixture of 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (1) (0.322 g, 1.2 mmol) in piperidine:acetic acid (30 μL:24 μL). The reaction mixture was heated in a 130° C. oil bath with efficient stirring for 1.5 hours. After cooling to room temperature, 2 mL of 1N HCl was added and the mixture stirred overnight. The mixture was made neutral with the addition of a saturated solution of NaHCO3 and then extracted into DCM (3×50 mL). The pooled extracts were washed sequentially several times with water, then brine, dried, filtered, and concentrated in vacuo to leave a dark brown oil. Purification by flash chromatography (silica gel, 135 g, 7% MeOH in DCM) afforded 0.075 g of the title compound as a light tan solid.
Reaction SMILES: [CH3:1][N:2]([C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].C1C=CC(P2([Se]P(C3C=CC=CC=3)(=[Se])[Se]2)=[Se:19])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:4](=[Se:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3]
Reactant: CN(N)C(=O)c1ccccc1
Reactant: [Se]=P1(c2ccccc2)[Se]P(=[Se])(c2ccccc2)[Se]1
Solvent: Cc1ccccc1
Product: CN(N)C(=[Se])c1ccccc1
Temperature: 25 °C
Yield: 194.7 %

Procedure:
A mixture of N-methylbenzohydrazide (450 mg, 3.0 mmol) and the Woollins' Reagent (540 mg, 1 mmol) in anhydrous toluene (10 ml), was heated at 120° C. for Ih. The resulting orange solution was cooled to room temperature, the solvent was removed in vacuo and the selenoamide purified by column chromatography on silica gel (3:1 Hexane:EtOAc) and to give N-methylbenzoselenohydrazide (415 mg) in 65% yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:17][C:18]1[S:26][C:21]2[S:22][C:23]([Br:25])=[CH:24][C:20]=2[C:19]=1[CH2:27]Br>>[Br:17][C:18]1[S:26][C:21]2[S:22][C:23]([Br:25])=[CH:24][C:20]=2[C:19]=1[CH2:27][N:15]1[CH2:16][CH:13]([CH2:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:14]1
Reactant: BrCc1c(Br)sc2sc(Br)cc12
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Product: O=S(=O)(CC1CN(Cc2c(Br)sc3sc(Br)cc23)C1)c1ccc(F)cc1

Procedure:
Prepared from 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4) and 2,5-dibromo-3-(bromomethyl)thieno[2,3-b]thiophene (Step 3) according to the method of Example 1 Step 5. 1H NMR (500 MHz, CDCl3) δ 7.90–7.88 (2H, m), 7.33 (1H, s), 7.26–7.23 (2H, m), 3.60 (2H, s), 3.40 (2H, t, J=7.4 Hz), 3.35 (2H, d, J=7.3 Hz), 2.90 (2H, t, J=7.0 Hz), 2.84–2.77 (1H, m); m/z (ES+) 540 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([O:22][C:23]([F:26])([F:25])[F:24])[CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[Na])(C)(C)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[C:4]([O:22][C:23]([F:26])([F:25])[F:24])[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2OC(F)(F)F)CC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCCC3)cc2OC(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl 4-[[4-bromo-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate (1.00 g, 2.28 mmol, 1.00 equiv), pyrrolidine (194 mg, 2.73 mmol, 1.20 equiv), t-BuONa (307 mg, 3.19 mmol, 1.40 equiv), Pd2(dba)3 (104 mg, 0.110 mmol, 0.05 equiv), BINAP (213 mg, 0.340 mmol, 0.150 equiv), toluene (20 mL). The resulting solution was stirred for 15 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with water (15 mL). The resulting solution was extracted with dichloromethane (3×15 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 940 mg (96% yield) of tert-butyl 4-[[4-(pyrrolidin-1-yl)-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate as light yellow oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: FC(F)(F)c1nnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C2CCN(c3nnc(C(F)(F)F)s3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole in dimethylsulfoxide at 85° C. in the presence of potassium carbonate. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[C:14]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:15][CH:16]=[CH:17][CH:18]=1.NN>CO>[NH2:3][CH2:12][C:13]1[C:14]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ncccc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methylcarbamate (30 g, 81 mmol) in MeOH (450 mL) at 0° C. was added hydrazine (25 mL, 810 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The precipitate was filtered off, and the filtrate was concentrated to dryness. The residue was triturated with dichloromethane (500 mL) and filtered. Concentration of the filtrate afforded tert-butyl (3-(aminomethyl)pyridin-2-yl)methylcarbamate in quantitative yield (18.7 g). LRMS (M+H+) m/z 238.1.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[C:9]([C:10]#[N:11])=[CH:8][N:7]([CH3:12])[N:6]=1.[ClH:20]>C(O)(C)C>[ClH:20].[NH2:11][C:10]1[C:9]2[C:5](=[N:6][N:7]([CH3:12])[CH:8]=2)[NH:4][C:3]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:2]=2[N:1]=1
Reactant: Cn1cc(C#N)c(Nc2ccc([N+](=O)[O-])cc2N)n1
Agent: Cl
Solvent: CC(C)O
Product: Cn1cc2c(n1)Nc1ccc([N+](=O)[O-])cc1N=C2N

Procedure:
3-(2-Amino-4-nitroanilino)-1-methylpyrazole-4-carbonitrile (250 mg) was heated under reflux in a mixture of isopropanol (10 ml) and concentrated hydrochloric acid (1 ml) for 20 hours. The solution was evaporated under reduced pressure and the residue crystallised from methylated spirits to give the title compound m.p. >260°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To 4-hydroxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (1.25 g, 5.45 mmol) and pyridine (0.661 mL, 8.18 mmol) in dichloromethane (10 mL) at 0° C. is added methanesulfonyl chloride (0.593 mL, 7.63 mmol). After 3 hours, one additional equivalent of methanesulfonylchloride and pyridine are added. After 1 hour the reaction mixture is concentrated, then EtOAc and water are added. The organic layer is concentrated and chromatographed on silica gel eluting with MeOH in dichloromethane 0-3% to give the title compound as a yellow oil (1.60 g, 95% yield).
Reaction SMILES: [O:1]1CCCC1.[CH2:6]([C:9]1[C:10]([Cl:35])=[N:11][C:12]2[N:13]([N:32]=[CH:33][CH:34]=2)[C:14]=1[N:15]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=C.I([O-])(=O)(=O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.O>[C:18]([O:17][C:16](=[O:22])[N:15]([C:14]1[N:13]2[N:32]=[CH:33][CH:34]=[C:12]2[N:11]=[C:10]([Cl:35])[C:9]=1[CH2:6][CH:7]=[O:1])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)([CH3:20])([CH3:19])[CH3:21]
Reactant: C1CCOC1
Reactant: C=CCc1c(Cl)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC=O)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixed solution of tetrahydrofuran (12 mL) and water (3 mL) containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (1.5 g, 3.5 mmol), sodium periodate (2.3 g, 10.5 mmol) and osmium tetraoxide (2.5w/v % in tert-butanol, 1.8 mL, 0.15 mmol) were added with ice-cooling. After this mixture was stirred at room temperature for 5 hr, aqueous sodium sulfite was added here. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain tert-butyl[5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:7]1=[O:16])C.O.[NH2:19][NH2:20]>C(O)C>[O:16]=[C:7]1[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=[CH:11][N:6]1[CH2:5][C:4]([NH:19][NH2:20])=[O:3]
Reactant: CCOC(=O)Cn1cccc(C(F)(F)F)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cn1cccc(C(F)(F)F)c1=O
Yield: 95 %

Procedure:
As described for example 112a, (2-oxo-3-trifluoromethyl-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 95%). MS: m/e=236.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.O.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CO>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Solvent: O
Solvent: CO
Product: CCCCCCCCOc1ccc2c(=O)c3ccc(O)cc3oc2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 30 %

Procedure:
3,6-Dihydroxy xanthone (1,20 mmol) was dissolved in hot mixture of basic water (80 mmol of Na2CO3 in 100 ml of water) and 50 ml of methanol. After the compound was completely dissolved, a methanol solution of octyl bromide (40 mmol in 50 ml of methanol) was added dropwise and the reaction mixture was stirred rigorously for 120 hours at refluxing temperature. The reaction mixture was cooled to room temperature giving a precipitate. This white precipitate was then filtered, washed with water, and washed with hot hexane to remove the disubstituted side product. 3-Octoxy-6-hydroxy xanthone was obtained in 30% yield. 1HNMR (DMSO): d11.0(1H,s), 8.05 (1H,d,J=6.0 Hz), 8.02 (1H,d,J=5.8 Hz), 7.08 (1H,s), 7.00 (1H,d,J=8.8 Hz), 6.89 (1H,d,J=8.8 Hz), 6.85 (1H,s), 4.43 (2H,t,J=6.2 Hz), 1.8(2H,M), 1.3 (10H,m), 0.9 (3H,t).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[O:9][CH2:8]1.[O:10]1CCCC1.Cl(O)(=O)(=O)=O>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH2:8][OH:10]
Reactant: C1CCOC1
Reactant: BrCCCCCC1CO1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: OCC(O)CCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 g of 1-bromo-6,7-epoxyheptane were introduced into a mixture of 400 ml of tetrahydrofuran and 235 ml of water, which had been adjusted to pH 2 with perchloric acid, at room temperature. After stirring at room temperature for 8 hours, the mixture was neutralized, evaporated under reduced pressure and the residue was extracted with methylene chloride. After removal of the solvent, 41.5 g of crude 1-bromo-6,7-dihydroxyheptane were obtained.