Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.N[C@@H](C1C=CC(OC)=C(OC)C=1)CC(OC)=O.C(=O)([O-])[O-].[Na+].[Na+].C(N1C(=O)C2=CC=CC=C2C1=O)(OCC)=O>>[C:4]1(=[O:22])[N:5]([C@@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:1](=[O:27])[C:2]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:3]12
Reactant: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: COC(=O)C[C@@H](N)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Product: COC(=O)C[C@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Prepared as described earlier as methyl 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionate from methyl (3R)-3-amino-3-(3',4'-dimethoxyphenyl)propionate (0.25 g, 0.91 mmol), sodium carbonate (0.10 g, 0.91 mmol) and N-carboethoxyphthalimide (0.20 g, 0.91 mmol). Methyl (3R)-3-phthalimido-3-(3',4'-dimethoxyphenyl)propionate was obtained as a white powder, 0.29 g (88%); 1H NMR (DMSO-d6, 250 MHz) δ 7.87 (br s, 4 H, Ar), 6.80-7.10 (m, 3 H, Ar), 5.64 (dd, 1 H, J1 =7 Hz, J2 =9 Hz), 3.73 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.55 (s, 3 H, OCH3), 3.30-3.67 (m, 2 H) ; 13C NMR (DMSO-d6) δ 170.8, 167.6, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.2, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal. Calcd for C20H19NO6 @0.80 H2O. Theoretical C, 62.60; H, 4.99; N, 3.69. Found C, 62.60; H, 4.93; N, 3.69. HPLC 99.9%.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[C:17](=[O:23])[N:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:13]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.C(O)C>[ClH:39].[CH3:22][N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:13]([S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:12]=[C:11]([CH2:10][NH:2][CH3:1])[CH:15]=2)[C:17]1=[O:23]
Reactant: CN(Cc1cc(-c2cccn(C)c2=O)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccn(C)c2=O)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
tert-Butyl methyl{[5-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (9.9 mg) was dissolved in ethyl acetate (0.5 mL) and ethanol (0.5 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. The residue was solidified with diisopropyl ether to give the title compound as a pale-gray solid (yield 5.7 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]12[CH2:9][C:5]([C:10]([NH2:12])=O)([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O.[OH-].[Na+]>O1CCCC1.CCOCC>[N:1]12[CH2:9][C:5]([CH2:10][NH2:12])([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: NC(=O)C12CCCN(CCC1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCC12CCCN(CCC1)C2
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A suspension of 1-azabicyclo[3.3.1]nonane-5-carboxamide (1.80 g, 10.7 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 1.0N lithium aluminum hydride/tetrahydrofuran (25 mL, 25 mmol), and the mixture was refluxed for 4 hours and cooled (0° C.). The mixture was treated carefully dropwise sequentially with water (1 mL), 15% sodium hydroxide (1 mL), and water (3 mL). Ether (50 mL) was added, the mixture was filtered through Celite, and the filter cake was washed with ether. The filtrate was concentrated in vacuo to afford 1.27 g (77%) of colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]([CH2:18][CH:17]=[CH2:16])([CH2:1][CH3:2])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: C=CCBr
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a stirred solution of diethyl ethylmalonate (43.0 mL, 0.228 mol) in THF (500 mL) at 0° C. was added sodium hydride (60%; 9.2 g, 0.228 mol) in portions. The mixture was warmed to rt and stirred at rt for 75 min, and was added allyl bromide (23.9 mL, 0.275 mol). The reaction was stirred at rt for 4 h, and then cooled to 0° C. and quenched with water (400 mL) and 6 N hydrochloric acid (80 mL). The product was extracted with diethyl ether (4×200 mL), and the extracts were washed with brine (2×200 mL), dried over sulfate and concentrated. The residue was distilled to give 2-allyl-2-ethylmalonic acid diethyl ester (b.p. 89-91° C./ca. 2 mm Hg).
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:3].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1>CC(C)=O>[CH3:3][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:1].[C:21]1([CH3:20])[CH:26]=[CH:25][C:24]([C:27]([O-:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)[O-])cc1

Procedure:
The S-atenolol having an optical purity of 96.5% ee (10.77 g) thus obtained and p-toluic acid (5.54 g) are dissolved in acetone (1 liter) by heating with stirring and the mixture is stirred at room temperature for 10 hours. The precipitated crystals are separated by filtration and the filtrate is concentrated under reduced pressure to give S-atenolol p-toluate having an optical purity of 98.5% ee (14.47 g).
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C@@H:14]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:17]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:16][C@H:15]1[C:45]1[CH:50]=[C:49]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N:61]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:54][C:53]=2[CH3:72])[C:48]([CH3:73])=[CH:47][C:46]=1[O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.NN.[OH-].[Na+]>CO>[NH2:61][CH2:60][CH2:59][O:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][C:49]2[C:48]([CH3:73])=[CH:47][C:46]([O:74][CH2:75][C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)=[C:45]([C@@H:15]3[O:16][C@H:17]([CH2:36][O:37][CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C@@H:18]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@H:19]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:14]3[O:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:50]=2)=[C:53]([CH3:72])[CH:54]=1
Reactant: Cc1cc(OCCN2C(=O)c3ccccc3C2=O)ccc1Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OCc2ccccc2)cc1C
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCN)ccc1Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OCc2ccccc2)cc1C
Temperature: 65 °C

Procedure:
To a tetrahydrofuran (0.8 mL) and methanol (0.2 mL) solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ethoxy]-2-methylbenzyl]-4-methylphenyl]-D-glucitol (60 mg, 0.059 mmol) was added hydrazine monohydrate (30 mg, 0.59 mmol), and the reaction mixture was stirred at 65° C. for an hour. After the mixture was cooled to room temperature, a 2 M aqueous solution of sodium hydroxide was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound quantitatively.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25]C)=[O:24])[CH:18]=2)=[CH:14][N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.C1COCC1>[CH3:5][C:3]([CH3:6])([O:7][C:8]([NH:10][C:11]1[S:12][C:13]([S:16][C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]([OH:25])=[O:24])=[CH:14][N:15]=1)=[O:9])[CH3:4]
Reactant: COC(=O)c1cccc(Sc2cnc(NC(=O)OC(C)(C)C)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(Sc2cccc(C(=O)O)c2)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1 N aqueous sodium hydroxide solution (50 mL, 50 mmol) was added dropwise to a stirred solution of 2-tert-butoxycarbonylamino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.8 g, (contaminated with bis(tert-butoxycarbonyl)amino adduct)) in a methanol-THF mixture (160 mL, 3:1). The solution was stirred at rt. for 24 h and concentrated. The residue was acidified with 2 N aqueous HCl (30 mL) and the suspension was extracted with dichloromethane-methanol mixture (120 mL, 3:1, 2×). The combined organic extract was dried (MgSO4), filtered and concentrated in vacuo to obtain the titled compound (1.32 g, 75% overall yield from Example 1, part A) as an off-white solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]=2[O:9][CH2:8][CH2:7]1>>[Cl:1][S:2]([C:13]1[CH:14]=[C:15]([C:16]([OH:18])=[O:17])[C:10]2[O:9][CH2:8][CH2:7][O:6][C:11]=2[CH:12]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cccc2c1OCCO2
Product: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Temperature: 55 °C
Yield: 93.4 %

Procedure:
670 g of chlorosulfonic acid were introduced into a balloon flask provided with a condenser and a thermometer. 173 g of 1,4-benzodioxane-5-carboxylic acid were added in portions with the temperature being maintained at 5°-10° C. The mixture was heated at 55° C. and then cooled and poured into ice. The precipitate was dried off, washed and dried again. 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 210°-215° C.; yield: 93.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:30])[C:12]([CH3:29])([CH3:28])[CH:13]([CH2:26][CH3:27])[NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:17]=2[F:24])[CH2:7][CH2:6]1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:30])[C:12]([CH3:28])([CH3:29])[CH:13]([CH2:26][CH3:27])[NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[NH:23])=[CH:18][C:17]=2[F:24])[CH2:7][CH2:6]1
Reactant: C1CCNC1
Reactant: CCC(NC(=O)c1ccc(C#N)cc1F)C(C)(C)C(=O)N1CCC(CC(=O)OC)CC1
Product: CCC(NC(=O)c1ccc(C(=N)N2CCCC2)cc1F)C(C)(C)C(=O)N1CCC(CC(=O)OC)CC1
Yield: 21 %

Procedure:
N-Boc-β-ethyl-α,α-dimethyl-β-alanine was condensed with 4-piperidineacetic acid methyl ester in the same manner as in Example 43 to yield N-(N-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid methyl ester. From the resulting compound, methyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate was derived in the same manner as in Example 45. The same procedure as in Example 45 was performed with this compound (1.0 g, 2.3 mmol) by using pyrrolidine (1.9 ml) as an amine to yield the titled compound (248 mg, 21%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=O.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:37](=[N:40]O)([NH2:39])[CH3:38]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]2[O:10][N:40]=[C:37]([CH3:38])[N:39]=2)[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: COCOc1cc(C(=O)O)ccc1C
Reactant: CC(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(-c2nc(C)no2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methoxymethoxy-4-methyl-benzoic acid (1.96 g, 10 mmol) (from Example 50 supra), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.92 g, 10 mmol) (Aldrich) and 1-hydroxybenzotriazole hydrate (1.35 g, 10 mmol) (Aldrich) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 30 minutes. Acetamide oxime (0.74 g, 10 mmol) (GFS Chemicals) was added and mixture heated at 140 C for 2 hours. After cooling, mixture was partitioned between ethyl acetate (2×) and saturated aqueous bicarbonate solution. Ethyl acetate solutions were combined and concentrated and residue purified by flash chromatography to give 5-(3-methoxymethoxy-4-methyl-phenyl)-3-methyl-[1,2,4]oxadiazole. (Yield 1.23 g, 52.5%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][CH:15]=1)C1C=CC=CC=1>>[N:1]1([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OCCc1ccc(OCc2ccccc2)cc1
Product: Oc1ccc(CCn2cncn2)cc1

Procedure:
In a manner analogous to that described in Example 10(b), from 1H-1,2,4-triazole and 1-benzyloxy-4-(2-methane-sulfonyloxyethyl)benzene, 4-[2-(1H-1,2,4-triazol-1-yl)ethyl]phenol was obtained.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([N:10]=[S:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:25][B-:26]([F:29])([F:28])[F:27].[CH3:30][O+](C)C>C(Cl)Cl>[F:25][B-:26]([F:29])([F:28])[F:27].[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7]([N:10]([S+:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:30])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N=S(c2ccccc2)c2ccccc2)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(C)[S+](c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
10.65 g (0.03 mol) of N-p-toluenesulfonyldiphenylsulfilimine were dissolved in 40 ml of dry methylene chloride, and 4.44 g (0.03 mol) of trimethyloxonium tetrafluoroborate were added. After stirring overnight and concentrating, the reaction product formed a crystalline precipitate. Drying under reduced pressure left 11.45 g of the salt (IV). Analysis and properties are indicated in Table 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:13])=[CH:7][C:6]=1[C:22]([F:24])([F:23])[F:25])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (50 mg, 0.13 mmol) in methylene chloride (1 mL) was treated with N,N-dimethylformamide (3 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.08 mL, 0.156 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (1 mL) and was treated dropwise with a solution of 2-aminothiazole (28 mg, 0.27 mmol) in tetrahydrofuran (1 mL) and 2,6-lutidine (0.08 mL, 0.65 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 7/3 hexanes/ethyl acetate to 6/4 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-N-thiazole-2-yl-propionamide (37 mg, 61%) as a white foam: EI-HRMS m/e calcd for C19H21F3N2O4S2 (M+H)+ 463.0968 found 463.0974.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C@H:24]([NH:34][CH3:35])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C@H:24]([N:34]([CH3:35])[C:10](=[O:11])[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([CH3:14])[CH3:13])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reactant: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2005002577) (0.146 g, 0.58 mmol) in CH2Cl2 (4 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (the preparation of which is described herein above) (0.15 g, 0.52 mmol) and ethyl-diisopropyl-amine (0.13 ml, 0.79 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 0.18 g (68%) of the title product as light brown oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[N:42]1[CH:41]=[CH:40][C:39]([CH2:38][NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])=[CH:44][CH:43]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2ccncc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccncc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-pyridin-4-ylmethyl-benzenesulfonamide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 619.2 [(M−H)−]; mp 251° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH:8]([OH:25])[CH2:9][N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH:8]([OH:25])[CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NCC(O)CN(Cc1ccccc1)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)NCC(O)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2-chloroacetyl chloride (1.25 g, 10.96 mmol) in CHCl3 was added to the solution of 1-amino-3-(dibenzylamino)propan-2-ol (2.5 g, 9.26 mmol) in CHCl3 (50 mL) in ice-bath. The mixture was stirred for 1 hour, then stirred at room temperature for 2 hours. The organic layer concentrated, the residue was purified by column to give white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH:11]([Si:14](Cl)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>CN(C=O)C.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(Br)ccc1Cl)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.8 %

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (425 mmol) in DMF (400 mL) was added imidazle (58 g, 850 mmol), 4-(dimethylamino)pyridine (2.6 g, 21 mmol), and triisopropylsilyl chloride (136 mL, 638 mmol). The resulting solution was stirred at ambient temperature for 15 h, diluted with a saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with water then brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to yield the titled compound 32 (152 g, 403 mmol, 95%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>[OH-].[Na+].CO>[OH:5][CH2:4][C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(O)c(CO)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
A solution of 2-hydroxy-5-nitrobenzaldehyde (5.01 g, 30 mmol) in a mixture of 60 mL 1M NaOH and 30 mL MeOH was cooled to 0° C. NaBH4 (1.13 g, 30 mmol) solution in 15 mL 1M NaOH and 5 mL MeOH was added slowly. The reaction mixture was stirred for 24 hours at room temperature. The mixture was poured into ice cooled 2M HCl and extracted with EtOAc. The organic layer was washed, dried, and evaporated in vacuo to give the alcohol as a yellow solid (5.1 g, 100%): MP (112-114° C.); 1H NMR (DMSO-d6, 400 MHz) δ 11.08 (s, 1H), 8.18 (d, 1H, J=2.5 Hz), 8.00 (dd, 1H, J=2.5 and 8.7 Hz), 6.92 (d, 1H, J=8.8 Hz), 5.20 (br, 1H), 4.49 (s, 2H).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1)=[O:2].[BH4-].[Na+]>CO.O>[OH:2][CH2:1][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 75a (74.5 mg, 0.223 mmol) was suspended in MeOH (10 mL) and then NaBH4 (26.3 mg, 0.695 mmol) was added. The reaction was stirred at rt for 18 h and then diluted with water (10 mL) and filtered. The solid was collected by filtration and the filter cake was washed with water (2×10 mL). The solid was dissolved in a mixture of DCM (100 mL) and MeOH (50 mL), dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to afford compound 75b. 1H-NMR (400 MHz, CD3OD+CDCl3) δ (ppm): 8.96 (d, J=2.2 Hz, 1H), 8.20 (dd, J=8.1, 2.2 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 4.79 (s, 2H), 4.29-4.36 (m, 4H), 3.85-3.94 (m, 4H). LCMS calcd for C17H16N6O2: 337.1 (M+H). found: 337.1.