Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.[CH3:20][CH2:21]N=C=NCCCN(C)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.C(O)C>[CH2:20]([O:14][C:13]([C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:11]=1)=[O:15])[CH3:21]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
Into a 500 mL flask was weighed 11.5 g (39.6 mmol) of 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid, 8.95 g (46.7 mmol) of EDCI, 530 mg (4.34 mmol) of DMAP, and 200 mL of CH2Cl2. Ethanol (8.6 mL) was then added to the stirred solution which was maintained at room temperature for 3 h. The reaction was then concentrated in vacuo to remove CH2Cl2. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 2×70 g Silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid ethyl ester as a viscous yellow oil, yield: 10.0 g (79.3%); 1H NMR (400 MHz, CDCl3): δ 7.32-7.46 (m, 4H), 7.19 (d, J=6 Hz, 1H), 4.16 (q, J=7 Hz, 2H), 1.13 (t, J=7 Hz, 3H); MS (ES): 319 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:28][C:29]([C:31]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:40]3[CH2:44][CH2:43][CH2:42][C@H:41]3[C:45](=[O:51])[NH:46][CH:47]3[CH2:50][CH2:49][CH2:48]3)=[O:39])[N:33]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:32]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][O:20]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(OCC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:28][C:29]([C:31]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:40]3[CH2:44][CH2:43][CH2:42][C@H:41]3[C:45](=[O:51])[NH:46][CH:47]3[CH2:48][CH2:49][CH2:50]3)=[O:39])[N:33]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[N:32]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccc(COCc2ccccc2)cc1
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCO)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h
Yield: 1.1 %

Procedure:
To a solution of 819 mg 4-[(S)-6-Benzyloxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-hexanoyl]-piperazine-1-carboxylic acid butyl ester in 20 ml ethyl acetate were added under argon 100 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 12 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give a mixture of the title compound (8 mg) and unreacted benzyl ether which was subjected to the same hydrogenolysis conditions described above to give the title compound.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]([N:9]=[N:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]>>[CH:6]([N:9]=[N:10][C:11]1([C:17](=[O:2])[NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CC(C)N=NC1(C#N)CCCCC1
Product: CC(C)N=NC1(C(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 100 ml of 96% sulfuric acid cooled to 0° C in an ice bath was added 13.5 grams (.0755 moles) of 1-isopropylazo-1-cyanocylohexane (from Example 4-b-6) dropwise over 1/2 hour while holding the temperature at 0° C. After the addition was complete the temperature was allowed to rise to 10° C over 1/2 hour and to 25° C over another 1/2 hour and then stirred another 1/2 hour at 25° C. The reaction mixture was poured onto 1/2 liter of ice and stirred until all of the ice dissolved. A white solid that formed was filtered off and the aqueous acid filtrate was extracted with 200 ml of methylene chloride. The methylene chloride extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure on a rotating evaporator. The product was a light brown liquid and weighed 5.0 grams (33.7% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-carbamylcyclohexane (strong broad carbonyl band at 1675-1750 cm-1 and NH band at 3500 cm-1).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:34]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)(=[O:36])=[O:35])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (84 mg, 69%), MS (ISP) m/z=487.4 [(M+H)+], mp 134° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:17])[CH:10]=[CH:11]1)[S:6]2.Cl.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:17])[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:11]1)[S:6]2
Reactant: COc1ccc2nc3ccc(=O)cc-3sc2c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)cc-3sc2c1
Temperature: 100 °C

Procedure:
A mixture of 7-methoxy-3H-phenothiazin-3-one (1.2 g) and N-methyl piperazine HCl (3.4 g) in DMF (20 ml) was heated at 100° C. for 3 hours. Then NaIO4 (1 g) was added and the reaction mixture was heated at 100° C. for 1 hour. Ice-water was added to the reaction mixture followed by ethyl acetate. The aqueous layer was decanted, filtered and the filtrate basified with K2CO3 and extracted with ethyl acetate. The organic layer was evaporated to dryness, the resulting residue was dissolved in CH2Cl2, dried and evaporated to dryness to afford the crude final product (1.2 g) which was purified by chromatography on silica gel column eluting with 10% MEOH/CH2Cl2 to give the title compound, m.p. 208°-209°.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH2:2][CH3:3].C1C(=O)NC(=O)N([C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@@H:23]2[OH:30])C=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CC>[C@@H:22]1([N:9]2[CH:8]=[N:7][C:6]3[C:10]2=[N:11][CH:12]=[N:13][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@@H:23]1[OH:30]
Reactant: CCCOc1ncnc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Solvent: CCCO
Product: CCCOc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 35 °C
Reaction time: 20 h
Yield: 43.6 %

Procedure:
6-n-Propoxypurine (5.6 mmoles, 1 g, Sigma Chemicals, St. Louis Mo.) was combined with 545 ml of a uracil arabinoside solution (10.1 mmoles) in 10 mM potassium phosphate and 7% n-propanol (v/v). Purified uridine phosphorylase (680 I.U.) and purine nucleoside phosphorylase (12000 I.U.) were added and the reaction stirred at 35° C. The reaction was filtered after 58 days and the filtrate stored at 3° C. for 20 hours. The resulting precipitate was collected by centrifugation, dissolved in 30% n-propanol/water (v/v), and chromatographed on a column of Dowex-1-formate resin (2.5×5 cm) after adjusting the pH to 10.5 with concentrated ammonium hydroxide. The column was eluted with 30% n-propanol/water (v/v) and fractions containing product were combined and solvent removed in vacuo. The residue was dissolved in n-propanol and chromatographed on a column containing BioRad P-2 (5×90 cm). The column was eluted with 30% n-propanol/water (v/v). Product-containing fractions were combined and after removing the solvent under vacuum the residue was dissolved in water and chromatographed on a column containing BioRad P-2 (5×90 cm). The column was eluted with water. Product containing fractions were combined and after lyophilization, yielded 0.758 g of 9-β-D -arabinofuranosyl-6-n-propoxy-9H-purine that analyzed as a monohydrate. NMR and mass spectrometry were consistent with the structure. Anal. Calcd. for C13H18N4O5.H2O: Calcd: C, 47.56; H, 6.14; N, 17.06. Found: C, 47.63; H, 6.13; N, 17.11.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[F:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1>CCCCCC.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[CH:24]=[N:23][CH:22]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1cncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Yield: 31 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-fluoropyridine-5-boronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the 31% of the title compound.
Reaction SMILES: Br.Cl.[Cl:3][CH2:4][CH2:5][NH2:6].[C:7]([NH:9][C:10](=[N:13][CH2:14]CCl)OC)#[N:8].CN>>[C:7]([NH:9][C:10]([NH:13][CH3:14])=[N:6][CH2:5][CH2:4][Cl:3])#[N:8]
Reactant: NCCCl
Reactant: COC(=NCCCl)NC#N
Agent: Br
Agent: CN
Agent: Cl
Product: CNC(=NCCCl)NC#N

Procedure:
Dimethyl-(N-cyanoimido)carbonate is a known compound. Its preparation was described e.g. in J. Org. Chem. 1974, 39, 1522. According to the process of Yugoslavian Application No. P-2151/83, dimethyl-(N-cyanoimido)carbonate is reacted with chloroethylamine hydrochloride hydrobromide to N-cyano-N'-(2-chloroethyl)-O-methyl-isourea, which is reacted with methylamine to yield the N-cyano-N'-methyl-N"-(2-chloroethyl)guanidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH2:12][C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:12]=[C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)Nc1ccccn1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(Nc3ccccn3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Pyridin-2-yl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=298.0 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][C@@H:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[NH:15][NH2:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:12]([O:11][C:9]([C@H:3]1[CH2:4][CH2:5][C@@H:6]([NH:16][NH:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@H:2]1[CH3:1])=[O:10])[CH3:13]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)[C@H]1CCC(=O)C[C@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@@H](NNC(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a 500-mL 3-neck round-bottomed flask was added (1S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (10.00 g, 54.3 mmol) in chloroform (201 ml). Then AcOH, glacial (3.13 ml, 54.3 mmol), and tert-butyl carbazate (7.89 g, 59.7 mmol) was added into the reaction mixture. The flask was placed into a pre-heated bath (30° C.) and allowed to stir 10 min. Then NaBH(OAc)3 (34.5 g, 163 mmol) was slowly added into the reaction mixture in small portions. The bath was removed after the addition and the overall mixture was allowed to stir under inert atmosphere 16 h. The progress of the reaction was monitored by LC/MS and TLC (30% EtOAc/DCM; Ninhydrin stain) which suggested reaction completion. The mixture was neutralized with the slow addition of sat. aq. NaHCO3 into the reaction mixture. After the material was neutralized, the layers were separated and the aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in-vacuo. The crude sample was analyzed by TLC (30% EtOAc/hexane; ninhydrin stain; Peak 1: Rf=0.46 & Peak 2: Rf=0.38) The crude material was divided into two portions and purified by chromatography through an Interchim (25 micron) silica-gel column (300 g)*(Two 300 Gram Columns were used), eluting with a gradient of 0-30% EtOAc in hexane, to provide tert-butyl 2-((1R,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (8.512 g, 28.3 mmol, 52.2% yield) (Peak 1; Cis)1H NMR (400 MHz, CDCl3) δ 6.03-6.28 (m, 1H), 4.07-4.16 (m, 2H), 3.59-3.90 (m, 1H), 2.76-2.97 (m, 1H), 2.55 (d, J=2.74 Hz, 1H), 2.01 (dd, J=3.03, 13.40 Hz, 1H), 1.59-1.77 (m, 3H), 1.49-1.56 (m, 2H), 1.46 (s, 10H), 1.19-1.31 (m, 3H), 1.02 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+ and tert-butyl 2-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)hydrazinecarboxylate (5.089 g, 16.94 mmol, 31.2% yield) (Peak 2; trans)1H NMR (400 MHz, DMSO-d6) δ 7.89-8.27 (m, 1H), 5.75 (s, 1H), 4.08-4.19 (m, 1H), 2.74-2.93 (m, 1H), 2.21-2.46 (m, 2H), 1.99 (s, 1H), 1.66 (d, J=3.91 Hz, 3H), 1.38 (s, 9H), 1.14-1.26 (m, 5H), 0.79 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 301.1 (M+H)+.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(NCCc1ccccc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-phenylethylamine as the starting materials.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:12]=[CH:11][NH:10][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.[F:13][C:14]1[C:19]([CH:20]=[O:21])=[C:18]([F:22])[CH:17]=[CH:16][C:15]=1[NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH:1]1([C:4]2[C:5]3[C:12]([CH:20]([OH:21])[C:19]4[C:14]([F:13])=[C:15]([NH:23][S:24]([C:27]5[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=5)(=[O:26])=[O:25])[CH:16]=[CH:17][C:18]=4[F:22])=[CH:11][NH:10][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: c1nc(C2CC2)c2cc[nH]c2n1
Product: O=S(=O)(Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(C4CC4)c23)c1F)c1ccc(C(F)(F)F)cc1

Procedure:
4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (44) was reacted with N-(2,4-difluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (10) similarly to the protocol of Example 4, Scheme 2, Step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[CH2:34]([C:41]1[O:45][CH:44]=[C:43]([CH2:46]Br)[CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:46][C:43]3[CH:42]=[C:41]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:45][CH:44]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Reactant: BrCc1coc(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1coc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (2.77 mmol) (as prepared in, for example, Example 1 or 2), potassium carbonate (3.25 mmol) and hexamethylphosphoric triamide (HMPT) (3 ml), with stirring and under nitrogen, at RT, is added 5-benzyl-3-furylmethyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hr and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and the solvent is removed from the filtrate. The residue is plated on prep. TLC plates developing with 10% ether/hexane to yield 5-benzyl-3-furylmethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.[Br:29]N1C(=O)CCC1=O.O>CC(O)=O>[Br:29][C:11]1[C:12]2[O:21][CH:20]3[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH:15]3[C:13]=2[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2Oc3c(Br)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Temperature: 25 °C
Reaction time: 27 h
Yield: 82 %

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (5.360 g, 12.750 mmol) was dissolved in 160 mL CH3COOH. N-Bromosuccinimide (4.539 g, 25.500 mmol) was added. The reaction mixture was stirred under N2 at rt for 27 h. The reaction mixture was poured into a mixture of 300 g ice and 100 mL water. The aqueous mixture was extracted with EtOAc (3×). The combined organic layers were washed with 5M NaOH (2×250 mL), 25% KOH (2×200 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was chromatographed (SiO2, 15% EtOAc:hexane), and tert-butyl 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was obtained in 82% yield (5.250 g, 10.516 mmol). MS (ESI+) for C22H22BrCl2NO3 m/z 499.8 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:19](N(OC)C)=[O:20])=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([Mg]Cl)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1>[C:19]([C:11]1[S:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:13][C:12]=1[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CON(C)C(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
Compound 134 (10.7 g, 30.3 mmol) was dissolved in THF (240 ml), and a THF solution of 2.0 mol/L phenylmagnesium chloride (60.6 mL, 121 mmol) was added thereto at 0° C. in an atmosphere of argon, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the entitled Compound 135 (6.18 g, 55%).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32]C)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH3:35]C1N=C(NC)N=C(C(O)=O)C=1.C(N)(=O)C>>[CH3:32][N:31]([CH3:35])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: CNc1nc(C)cc(C(=O)O)n1
Agent: CC(N)=O
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)nc(N(C)C)n1

Procedure:
rac-N-(3-{4-[5-(2-Dimethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 6-methyl-2-methylamino-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.94 min; [M+H]+=457.31.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[Li]CCCC.N#N.CCOCC.[C:22]([O:26][C:27](=[O:34])[NH:28][C@H:29]([CH:32]=[O:33])[CH2:30][CH3:31])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:34])[NH:28][C@H:29]([CH:32]([OH:33])[C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:30][CH3:31])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: c1cnc2ncoc2c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Temperature: -45 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Alternative procedure: To a stirred solution of the oxazolo[4,5-b]pyridine (12 g, 100 mmol) in THF (300 ml) was added n-BuLi (1.6M solution in 62.5 ml of hexane) drop wise under N2 at −78° C. After 1 hour, MgBr.Et2O (25.8 g, 100 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 hour before being treated with (S)-(1-formyl-propyl)-carbamic acid tert-butyl ester (11.46 g, 60 mmol) in THF (50 ml). The reaction mixture was stirred for 1 hour, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to yield (S)-[1-(hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbamic acid tert-butyl ester (14.1 g).