Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:26])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][CH:22]([OH:25])[C:23]#[CH:24])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:26][N:13]([CH3:12])[C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](=[O:25])/[CH:23]=[CH:24]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#CC(O)C=Cc1ccc(N(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(/C=C/C(=O)/C=C/c2ccc(C(F)(F)F)cc2)cc1
Temperature: 120 °C

Procedure:
4-iodobenzotrifluoride (150 μL, 1 mmol), 1-(4-(dimethylamino)phenyl)pent-1-en-4-yn-3-ol (242 mg, 1.2 mmol), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.02 mmol), copper iodide (3 mg, 0.03 mmol) and triphenylphosphine (52 mg, 0.2 mmol) were introduced in a 10 mL microwave vial flushed with argon. This was diluted with anhydrous triethylamine (700 μL, 4 mmol) in anhydrous degased 1,4-dioxane (1.3 mL). The solution was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was poured into brine (20 mL), and this was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to give crude product which was purified by flash chromatography (SiO2, 30% ethyl acetate in dichloromethane). The resulting yellow solid was triturated in diethyl ether to give pure final compound TG009A94 as a bright orange powder (200 mg, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22]SC)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][Cl:28])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCOc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2ccc(OCCl)cc2C1
Reaction time: 1 h

Procedure:
To a solution of 7-methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (200 mg) in methylene chloride (4 ml) was dropwise added sulfuryl chloride (0.052 ml) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated azeotropically with toluene and the residue was dried under reduced pressure to give the title compound (213 mg).
Reaction SMILES: CS(C)=O.N#N.C(Cl)(=O)C(Cl)=O.[OH:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C@H:21]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:22][N:23]([CH3:34])[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:16][CH2:15]1>C(Cl)Cl>[CH3:34][N:23]([CH2:22][C@@H:21]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:20][CH:17]1[CH2:18][CH2:19][C:14](=[O:13])[CH2:15][CH2:16]1)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: CN(C[C@H](CC1CCC(O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: N#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C[C@H](CC1CCC(=O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -65 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
A solution of DMSO (0.82 g, 10.47 mmol) in 10 mL of dry CH2Cl2, under protection of N2, was cooled to −78° C., followed by the slow, dropwise addition of oxalyl chloride (0.664 g, 5.23 mmol). After addition the mixture was stirred 2 hr at −65° C., then the solution of (S)-tert-butyl 1-(4-hydroxycyclohexyl)-3-(N-methyl-N-(benzyloxycarbonyl)amino)propan-2-ylcarbamate (1.1 g, 2.62 mmol) was added dropwise. After addition, the mixture was stirred 3 hr at −30° C. The reaction was quenched with Et3N (4 mL) and stirred 10 min, then saturated NaHCO3 (10 mL) was added. The aqueous layer was extracted 3 times with CH2Cl2 (3×20 mL). The CH2Cl2 layer was washed with 10% citric acid solution (20 mL), followed by saturated NaHCO3, brine, then dried over Na2SO4. After filtration, solvent removal gave crude product (1 g), which was purified by preparative TLC to give (S)-tert-butyl 1-(N-methyl-N-(benzyloxycarbonyl)amino)-3-(4-oxocyclohexyl)propan-2-ylcarbamate (500 mg, 1.2 mmol).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O1[C:16]2([CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[NH:30][C:31]3[C:32]4[C:39]([CH3:40])=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:18][CH2:17]2)[O:15]CC1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:29][C:27]1[CH:26]=[CH:25][C:24]([NH:30][C:31]2[C:32]3[C:39]([CH3:40])=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[C:23]([O:22][CH:19]2[CH2:20][CH2:21][C:16](=[O:15])[CH2:17][CH2:18]2)[CH:28]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC4(CC3)OCCO4)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC(=O)CC3)c2c1C

Procedure:
1.000 g p-toluenesulfonic acid was added to 0.500 g methyl 4-(2-(1,4-dioxaspiro[4.5]decan-8-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (cpd.19.1) in 10 ml THF and 5 ml water. After refluxing overnight the reaction mixture was adjusted to pH 8 using aq. Na2CO3. The aq. layer was extracted with chloroform. The combined extracts were passed through a hydrophobic frit and concentrated to give the desired compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[NH:11][N:10]=1.[CH3:26]I>>[CH3:26][N:10]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:24])[F:25])=[N:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:21])([F:22])[F:23])=[N:11]1
Reactant: FC(F)(F)c1ccccc1-c1n[nH]c(-c2ccccc2C(F)(F)F)n1
Reactant: CI
Product: Cn1nc(-c2ccccc2C(F)(F)F)nc1-c1ccccc1C(F)(F)F

Procedure:
starting from 3,5-di(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole and methyl iodide there is obtained 1-methyl-3,5-di(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 108°-111° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[OH:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[F:11]
Reactant: Nc1cc(Br)cc(F)c1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Nc1cc(Br)cc(F)c1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-bromo-6-fluorophenol (473 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O.CC(=O)OCC>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc(C=O)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (25.0 g, 152 mmol) in acetonitrile (250 mL), K2CO3 (42.1 g, 305 mmol) followed by benzyl bromide (26.0 g, 152 mmol) is added. The suspension is stirred at 60° C. for 18 h. The mixture is diluted with water (150 mL) and EA (150 mL). The org. extract is separated and the aq. phase is extracted once more with EA (100 mL). The combined org. extracts are washed with water (150 mL) and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (27.2 g) as a yellow oil; LC-MS: tR=1.09 min; 1H NMR (D6-DMSO): δ1.19 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.70 (q, J=7.5 Hz, 2H), 4.90 (s, 2H), 7.37-7.41 (m, 1H), 7.42-7.46 (m, 2H), 7.49-7.52 (m, 2H), 7.65-7.69 (m, 2H), 9.92 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[CH2:9][CH2:10][O:11][C:12]2[C:13]([OH:25])=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=2[O:18][CH3:19])=[CH:4][CH:3]=1.CS(O[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:26])[CH2:9][CH2:10][O:11][C:12]2[C:13]([O:25][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=2[O:18][CH3:19])=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)c(C(C)=O)c(O)c1OCCC(C)c1ccc(F)cc1
Reactant: CS(=O)(=O)OCCc1ccccn1
Product: COc1c(C)c(C)c(C(C)=O)c(OCCc2ccccn2)c1OCCC(C)c1ccc(F)cc1
Yield: 43 %

Procedure:
Example 4e (100 mg, 0.28 mmol) was reacted with 2-pyridin-2-ylethyl methanesulfonate (1.6 eq.) as described under General Procedure F to give the title compound (56 mg, 43%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J=4.2 Hz, 1H), 7.57 (dt, J=7.7, 1.8 Hz, 1H), 7.19-7.09 (m, 4H), 6.96-6.91 (m, 2H), 4.34 (t, J=6.6 Hz, 2H), 3.83 (t, J=6.6 Hz, 2H), 3.73 (s, 3H), 3.11 (6.6 Hz, 2H), 2.99-2.92 (m, 1H), 2.26 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.95-1.88 (m, 2H), 1.25 (d, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]3=[O:29])[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:30])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.[Cl-].[S:32](=[CH2:35])(=[O:34])=[O:33]>C(Cl)Cl>[CH3:35][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]3=[O:29])[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:30])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)(=[O:34])=[O:33]
Reactant: C=S(=O)=O
Reactant: C[C@]12C[C@H](c3ccc(CCCO)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@]12C[C@H](c3ccc(CCCOS(C)(=O)=O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Temperature: 2.5 °C

Procedure:
To a solution of 3.41 g of 11β-[4-(3-hydroxypropyl)phenyl]estra-4.9-diene-3,17-dione prepared to preparation 1 in 30 ml of CH2Cl2, under inert atmosphere and at ambient temperature, 1.53 ml of TEA and 0.72 ml of sulfonyl methane chloride in solution in 2 ml of CH2Cl2 is added whilst maintaining the temperature at 0-5° C. and stirring at this temperature. After washing and drying it is evaporated under reduced pressure until 4.15 g of expected raw product is obtained.
Reaction SMILES: Cl[C:2]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([Cl:26])=[CH:19][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>C1COCC1>[Cl:26][C:20]1[CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:2]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([Cl:27])[CH:29]=2)=[C:3]([CH:19]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cc([N+](=O)[O-])c2Cl)cc1
Reactant: NCc1cccc(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cc([N+](=O)[O-])c2NCc2cccc(Cl)c2)cc1

Procedure:
Methyl 4-{(1S)-1-[(2,5-dichloro-3-nitrobenzoyl)amino]ethyl}benzoate (500 mg, 1.26 mil) and 3-chlorobenzyl amine (1089 mg, 7.69 mmol) were dissolved in 50 ml THF. The mixture was refluxed overnight then cooled. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. 1H NMR (400 MHz, DMSO): δ 9.25 (d, 1H), 8.20 (t, 1H), 8.15 (s, 1H), 7.95 (d, 2H), 7.70 (s, 1H), 7.60 (d, 2H), 7.30 (m, 2H), 7.15 (s, 1H), 7.05 (d, 1H), 5.10 (m, 2H), 4.10 (m, 2H), 4.85 (s, 3H), 1.45 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[CH3:22])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[CH3:22])[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC(C)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: CCOC(=O)c1ccc(NC(=O)C(CC(C)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
222 mg (purity 85%, 0.50 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoic acid (mixture of racemic diastereomers) and 91 mg (0.55 mmol, 1.1 eq.) of ethyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 180 mg (purity 91%, 63% of theory)
Reaction SMILES: [BH4-].[Na+].[NH:3]1[CH:7]=[N:6][C:5](/[CH:8]=[C:9]2\[CH2:10][N:11]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][C:14]\2=[O:15])=[N:4]1.ClCCl>CO>[NH:3]1[CH:7]=[N:6][C:5](/[CH:8]=[C:9]2\[CH2:10][N:11]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH:14]\2[OH:15])=[N:4]1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nc[nH]n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nc[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Sodium borohydride (131 mg) was added to a solution of (E)-3-[(1,2,4-triazol-3-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (2.92 g) in a mixed solvent of dichloromethane (60 ml) and methanol (60 ml) at 0° C. After the mixture was stirred at room temperature for 30 minutes, the reaction was quenched by addition of a saturated aqueous ammonium chloride solution. Products were extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Solvents were removed under reduced pressure to afford crude (E)-3-[(1,2,4-triazol-3-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol. The crude product was dissolved in acetonitrile (60 ml) and methyl bromoacetate (920 μl) was added. After DBU (1.25 ml) was added thereto under cooling at 0° C., the mixture was stirred at 0° C. for 15 minutes. Water and ethyl acetate were added to the mixture and the layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure gave an approximately 1:3 mixture of the two title isomers (2.98 g, yield: 87%) as a pale yellow amorphous solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl>C1COCC1>[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:16])=[O:17])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a suspension of sodium hydride (314 mg, 7.86 mmol) in 8 mL of THF was added a mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (3.0 g, 6.55 mmol) and chloromethyl methyl ether (0.741 mL, 9.825 mmol) in 8 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 2.70 grams of the title compound as a white solid. (M+H)+ expect 502.0. found 502.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.ClCCCl.C(Cl)Cl.[OH-].[Na+]>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C=O)cc1
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CN2CCC(CO)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-piperidinemethanol (2.28 g, 19.78 mmol) and 4-methoxybenzaldehyde (2.30 mL, 19.77 mmol) in THF/DCE (1:1 by volume, 100 mL) was added acetic acid (1 mL), followed by NaBH(OAc)3 (16.76 g, 79.08 mmol) in small portions. The reaction mixture was stirred at room temperature overnight under N2. The reaction was diluted with DCM and basified to pH=10 with 2 N NaOH solution. The organic layer was separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (Eluent: 60% EtOAc in hexanes) to give the title compound as a pale yellow oil (2.13 g, 46%). 1H NMR (400 MHz, DMSO-d6) δ 1.04-1.13 (m, 2H), 1.28-1.32 (m, 1H), 1.58-1.61 (m, 2H), 1.79-1.86 (m, 2H), 2.75-2.77 (m, 2H), 3.22 (t, J=8.0 Hz, 2H), 3.34 (s, 2H), 3.72 (s, 3H), 4.38 (t, J=4.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H). MS 236 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:20]=[C:16]2[N:15]=[C:14]([CH3:26])[C:13]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C1(C2[O:41]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:20]=[C:16]2[N:15]=[C:14]([CH3:26])[C:13]=1[CH:27]([OH:41])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(Cl)n2n1
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a stirred solution of 0.9M KHMDS (40.9 mL, 36.8 mmol) in THF (100 mL) at −78° C. was added a THF (50 mL) solution of ethyl 7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (10 g, 30.7 mmol, for synthesis see WO2013025584) was added over the course of 20 min. After 30 min, a THF (15 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (10.43 g, 39.9 mmol) was added to the red reaction mixture and stirring was continued for an additional 30 min at −78° C. Then, the resulting orange reaction mixture was quenched with sat. aq. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a solid. This solid was triturated with small amount of ethyl acetate and solids were filtered, washed with hexanes and dried under high vacuum to afford ethyl 7-chloro-6-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5 g, 16.85 mmol, 43% yield, 90% pure) as light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 5.76 (s, 1H), 4.58-4.49 (m, 2H), 4.33 (dtt, J=10.7, 7.1, 3.7 Hz, 2H), 2.71-2.64 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.29-1.24 (m, 3H). LCMS (M+1)=342.16.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (5 g, 50.00 mmol) in methylene chloride (20 mL) was added 4-methylbenzene-1-sulfonyl chloride (9.4 g, 49.21 mmol). Triethylamine (15 g, 148.51 mmol) was added and the resulting solution was stirred overnight. Water (50 mL) was added and the resulting solution was extracted with methylene chloride (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 10 g (78.7%) of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[F:25])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[C:29]([CH3:40])[C:28]=1[CH3:41]>>[F:25][C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[C:21]([F:22])[C:16]=1[C:8]1[C:7]([CH2:6][O:5][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([CH3:40])[C:28]=2[CH3:41])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=1
Reactant: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(2,6-difluoro-4-methoxyphenyl) isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 6.93 (d, J=8.4 Hz, 1H), 6.52-6.59 (m, 3H), 5.02 (s, 2H), 3.85 (s, 3H), 2.94 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.20 (s, 3H), 1.97 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H20F5NO4S, 502.1 (M+H). found 502.1.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)[CH2:2][CH:3]=[CH2:4].I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][O:29][CH3:30]>>[CH3:30][O:29][CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:4][CH2:3][CH2:2][CH2:1][N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH2:6]1
Reactant: COCOc1ccccc1I
Reactant: C=CCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1
Product: COCOc1ccccc1CCCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1

Procedure:
The title compound, MS: m/e=420.3 (M+H+) was prepared from (RS)-4-(1-but-3-enyl-pyrrolidine-3-sulfonyl)-phenol and 1-iodo-2-methoxymethoxy-benzene. 1-Iodo-2-methoxymethoxy-benzene is a known compound and has been prepared as described in the following reference: J. R. Labrosse; C. Poncet; P. Lhoste; D. Sinou; Tetrahedron, Asymmetry; 10; 6; 1999; 1069-1078.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH:7]1([C:12](O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>O>[NH2:1][N:2]1[C:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:6][N:5]=[C:3]1[SH:4]
Reactant: NNC(=S)NN
Reactant: O=C(O)C1CCCC1
Solvent: O
Product: Nn1c(S)nnc1C1CCCC1
Temperature: 165 °C

Procedure:
34.29 g (323 mmol) of finely mortared thiocarbohydrazide are suspended in 38.5 ml (355.3 mmol) of cyclopentanecarboxylic acid and the suspension is heated at 165° C. for 20 min. During this, the water produced in the reaction is distilled off until a yellowish condensate appears. After cooling down, 250 ml of dichloromethane/methanol 95:5 are added to the suspension and the precipitate is filtered off. The filtrate is concentrated and subject to column filtration on silica gel (dichloromethane/methanol 98:2). After drying under high vacuum, the product is obtained as a colorless solid.