Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Cl[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=1.Cl>CS(C)=O>[OH:19][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][C:14]=1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1cc(CNS(C)(=O)=O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 1.60 g, 40.0 mmol) in 25 mL DMSO under Argon was added dropwise a solution of methanesulfonamide (3.80 g, 40.0 mmol) in 10 mL DMSO. The resulting mixture was stirred 30 minutes and a solution of 5'-(chloromethyl)-2'-hydroxyacetophenone (3.69 g, 20.0 mmol) in 10 mL DMSO was added. The resulting mixture was stirred three hours, poured into 150 mL ice water, acidified with 14 mL 3N hydrochloric acid, and the mixture extracted with methylene chloride (3×200 mL). The extract was washed with water (50 mL) and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give an oil which was partially purified by flash chromatography eluting with 3:97 methanol:chloroform to give a gum. The gum was stirred under 25 mL water to remove residual DMSO, the aqueous supernatant was decanted, and the residue was dried in vacuo. The resulting material was crystallized from ethylacetate to remove 0.67 g of a by-product identified as N,N-bis[(3-acetyl-4-hydroxyphenyl)methyl]methanesulfonamide. The mother liquor was concentrated in vacuo to give a residue which was re-chromatography to give a solid. The solid was recrystallized from n-butylchloride to give 0.60 g (12%) product, as a white solid, mp 85°-86.5° C.
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[F:7][C:8]([F:24])([F:23])[C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:13][CH:14]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[F:24][C:8]([F:7])([F:23])[C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:20][CH:21]=2)=[N:13][CH:14]=1
Reactant: CC(Cl)C(=O)O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
100.0 g (0.92 mol) of (RS)-(+)-2-chloropropionic acid are added to the solution of 192.0 g (0.75 mol) of 4-(5-trifluoromethyl-2-pyridyloxy)phenol in 900 g (about 1050 ml) of xylene. The temperature of the reaction mixture is elevated to 80° C. and 78.0 g (1.95 mol) of sodium hydroxide dissolved in water are added dropwise under such a reduced pressure (about 36 kPa) that the mixture boils at 90° C. The water formed in the reaction is continuously distilled off while maintaining the boiling temperature at 90° C. After the addition, the reaction mixture is stirred at 90° C. for additional 15 minutes, then the reduced pressure is ceased. After adding 300 ml of water to the mixture and stirring at 85° C. for 10 minutes, it is acidified by adding phosphoric acid and the phases are separated. The xylene layer is dried, treated with activated charcoal and finally evaporated to dryness.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC([C@@H]2C(=O)[N:39]([C@@H:42]([C@H:55]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH3:56])[C:43]([NH:45][C:46]3[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=3)=[O:44])C(=O)N2)=CC=1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:11])[NH:39][C@H:42]([C:43](=[O:44])[NH:45][C:46]1[S:47][CH:48]=[C:49]([C:51](=[O:54])[CH2:52][CH3:53])[N:50]=1)[C@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH3:56])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCN2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (740 mg, ≈1.96 mmol) was dissolved in tetrahydrofuran (30 mL) and (2S,3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (250 mg, 0.78 mmol) (prepared as described in example 4) was added followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 3.5 hours additional (R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (320 mg, ≈0.85 mmol) was added to the reaction mixture. After stirring for an additional 1.5 hours an additional aliquot of (R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (300 mg, ≈0.82 mmol) was added to the reaction mixture along with additional 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (90 mg, 4.72 mmol). After stirring at room temperature for an additional 1 hour the mixture was partitioned between ethyl acetate and brine, the organic extract was dried over sodium sulfate, concentrated in vacuo and the resulting residue purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. {(R)-[(1S,2S)-2-Phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-carbamic acid tert-butyl ester was obtained as a white solid (120 mg, 24%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=O>C(O)(=O)C>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[CH:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)[N:3]2[N:4]=1)[CH3:8]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: CCc1nc2nccc(-c3cccc(C(F)(F)F)c3)n2n1

Procedure:
A mixture of 2.24 g. of 3-amino-5-ethyl-1,2,4-triazole and 4.86 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 50 ml. of glacial acetic acid is refluxed for 16 hours. The resulting mixture is worked up as described in Example 54 to give the product of the Example, m.p. 132°-134° C.
Reaction SMILES: O.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([NH:18][C:19](=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])SC)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:26]([O:25][C:23]([NH:22][C:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[N:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[CH:4][CH:5]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(=NCc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
4-hydroxybenzylamine hydrate, prepared as above (5.33 g) and N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (10.96 g) were combined in 150 mL THF, and stirred at reflux for 4 hr. The mixture was concentrated, and the crude product chromatographed on silica gel with 10% ethyl acetate in dichloromethane. Recrystallization from methanol-water provided the title compound as a white solid, mp 187°-189° C. (10 g, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:32]#[N:33])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:6][CH:7]=1.CS(C)=[O:43]>>[CH:25]1([CH2:24][N:20]([CH2:21][CH2:22][CH3:23])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][N:8]([CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:32]#[N:33])[C:5]2[N:4]=[CH:3][C:2]([OH:43])=[CH:7][N:6]=2)[CH2:27][CH2:26]1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CS(C)=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
3-({(5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-methyl)-5-trifluoromethyl-benzonitrile (2.81 g) is dissolved in dimethylsulfoxide (12.6 ml) and the mixture is degassed under reduced pressure and flushed with nitrogen gas. Thereto are added potassium acetate (1.32 g), bis(pinacolato)diboron (2.88 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (732 mg) and the mixture is heated at 80° C. under nitrogen atmosphere and stirred for 1 hour and 40 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (26 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (15.7 ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-{[[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (1.94 g). MS (m/z): 564 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([NH2:18])=[S:17])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Br.CS(C)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: COc1cnc(N2CCOCC2)cc1NC(N)=S
Agent: Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cnc(N2CCOCC2)c2sc(N)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a stirred suspension of 3.51 g (13.1 mmol) (5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea in 75 ml ethyl acetate heated to reflux was added dropwise over 5 min 4.59 ml (26.2 mmol) hydrobromic acid (5.7 M solution in acetic acid) and stirring continued for a further 15 min. 1.12 ml (15.7 mmol) DMSO was then added dropwise and the reaction mixture stirred for a further 30 min at reflux. The mixture was then cooled to room temperature and partitioned between tetrahydrofuran and saturated brine. 5 N sodium hydroxide solution was added until the aqueous phase was pH 14, then 10% aq. citric acid solution was added until the aqueous phase was pH 6. The mixture was stirred for 20 min and then the phases were separated. The organic phase was dried over sodium sulfate and concentrated in vacuo. Trituration of the residue in ether afforded 2.23 g (64%) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine as an off-white crystalline solid. ES-MS m/e (%): 267 (M+H+, 100).
Reaction SMILES: [CH:1]1([N:6]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]3[C:7]2=[N:8][C:9]([NH:19][C:20]2[CH:42]=[CH:41][C:23]([C:24]([NH:26][CH:27]4[CH2:33][CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)=[O:25])=[CH:22][C:21]=2[O:43][CH3:44])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH:27]([NH:26][C:24](=[O:25])[C:23]2[CH:41]=[CH:42][C:20]([NH:19][C:9]3[N:8]=[C:7]4[C:12]([N:13]([CH3:18])[C:14](=[O:17])[CH2:15][CH2:16][N:6]4[CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][N:10]=3)=[C:21]([O:43][CH3:44])[CH:22]=2)[CH2:28]1
Reactant: COc1cc(C(=O)NC2CCCCN(C(=O)OC(C)(C)C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 3-[[4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoyl]amino]azepane-1-carboxylate (Example 348; 149 mg, 0.25 mmol) in DCM (2 mL) was treated with TFA (1 mL) The resulting solution was stirred at ambient temperature for 5 hours.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)N)=[O:8])=[CH:5][CH:4]=1.[C:22]([OH:29])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O>O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:11]3[C:16](=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[C:24]([CH2:23][C:22]([OH:29])=[O:28])=[C:25]2[CH3:27])=[O:8])=[CH:5][CH:4]=1
Reactant: NN(C(=O)c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: O
Product: Cc1c(CC(=O)O)c2cc3c(cc2n1C(=O)c1ccc(Cl)cc1)OCO3
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 1.9 g of N1 -(p-chlorobenzoyl)-3,4-methylenedioxyphenylhydrazine hydrochloride and 20 g of levulinic acid was heated for 1 hour at 55° - 60°C and for 3 hours at 80° - 90°C. The reaction mixture was cooled to a room temperature, and poured into 200 ml of water. The precipitates were collected by filtration and washed with water. The crystals obtained by twice recrystallizing from acetone-water (5 : 1) gave 1.19 g of 1-(p-chlorobenzoyl)-2-methyl-5,6-methylenedioxy-3-indolylacetic acid having a melting point of 217° - 218°C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][N:29]=[N+]=[N-])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][NH2:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reaction time: 2 h

Procedure:
5-(2-Azidomethyl-pyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (165 mg, 0.36 mmol) is dissolved in THF (5 mL) at 0° C. and lithium aluminum hydride (0.55 mL, 0.55 mmol, 1.0M THF solution) is added. After 2 h, the mixture is quenched with water before extraction with EtOAc. The organic layer is washed with saturated aqueous NH4Cl and then dried over anhydrous Na2SO4. Following concentration the residue is separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 427.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.39 (m, 2 H), 8.15 (d, J=3.8 Hz, 1 H), 8.09 (s, 1 H), 7.97 (d, J=8.1 Hz, 1 H), 7.64 (t, J=8.0 Hz, 1 H), 7.50 (d, J=7.6 Hz, 1 H), 7.45 (d, J=2.5 Hz, 1 H), 7.12 (dd, J=8.8, 2.5 Hz, 1 H), 7.00 (s, 1 H), 6.81 (d, J=3.3 Hz, 1 H), 6.76 (d, J=3.5 Hz, 1 H), 3.76 (s, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].ICC.[Cl-].[NH4+]>C1COCC1>[CH2:19]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1)[CH3:20]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
0.2 g (0.78 mmol) of tert-butyl 4-ethoxycarbonylpiperidine-1-carboxylate is dissolved in 4 mL of THF at −10° C. 0.8 mL (1.56 mmol) of lithium diisopropylamide is added dropwise. After 15 minutes, 0.09 mL (1.2 mmol) of iodoethane is added and the mixture is warmed to room temperature. It is stirred for 30 minutes and then poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried and then concentrated to dryness. The oil obtained is chromatographed on silica gel (eluent: 95/5 heptane/ethyl acetate). 183 mg of tert-butyl 4-ethyl-4-ethoxycarbonylpiperidine-1-carboxylate in the form of a yellow oil are obtained in a yield of 82%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[O:29][CH3:30].[CH2:31]([O:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:17][C:18](=[O:28])[C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=2[O:29][CH3:30])=[O:44])=[CH:46][CH:47]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)ccc1O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc([N+](=O)[O-])cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of tert-butyl 3-(4-hydroxy-3-methoxyphenyl)-2-(4-nitrobenzamido)propanoate INT-7 (1.34 g, 3.05 mmol) and TEA (1.28 mL, 9.15 mmol) in DCM (8 mL) at 0° C. was added 4-(heptyloxy)benzoyl chloride (0.81 mL, 3.36 mmol) dropwise. After warming to room temperature and stirring for 1 h, the mixture was quenched with saturated aqueous NaHCO3 (100 mL) and diluted with DCM (100 mL). The organic layer was dried over MgSO4 and concentrated. The product was purified by chromatography (EA/hexanes) to afford 1.70 g (86%) of 4-(3-(tert-butoxy)-2-(4-nitrobenzamido)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-8. LCMS-ESI (m/z) calculated for C35H42N2O9: 634; no mass ion observed, tR=3.26 min (Method 4).
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:2][O:1][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9]1
Reactant: OCCCCC(O)CO
Reactant: COC(OC)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: OCCCCC1COC(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 60 h
Yield: 27.8 %

Procedure:
A mixture of 1,2,6-trihydroxyhexane (2.58 g) and benzaldehyde dimethyl acetal (3.18 g) is treated with toluene sulfonic acid hydrate (2.08 g). The mixture is allowed to stir at room temperature for 60 hours, and is then partitioned between saturated aqueous sodium bicarbonate (50 ml) and methylene chloride (20 ml). The benzaldehyde dimethyl acetal (3.18 g) is treated with toluene sulfonic acid hydrate (2.08 g). The mixture is allowed to stir at room temperature for 60 hours, and is then partitioned between saturated aqueous sodium bicarbonate (50 ml) and methylene chloride (20 ml). The layers are separated, the aqueous layer is re-extracted with methylene chloride, the organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated to an oil (2.66 g), which is purified by column chromatography (silica gel, 1:1 ethyl acetate/hexanes). Pooling and concentrating the appropriate fractions give the title compound as an oil (1.19 g): TLC Rf =0.18 (silica, 1:1 ethyl acetate/hexanes); 1H NMR (CDCl3), δ, 1.62 (m, 6H), 3.67 (m, 3H), 3.25 (m, 2H), 6.37 (s, 0.6H), 6.50 (s, 0.4H), 8.04 (br. s, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:13][CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)N
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CO
Product: CC(C)Nc1cc(Cl)nc(N)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
In a 25 mL sealable tube under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and isopropylamine (0.78 mL, 9.15 mmol) in CH3OH (15 mL). The vial was sealed and the resulting mixture was stirred overnight at 50° C. The reaction was cooled to room temperature and stirred over the weekend. The reaction mixture was concentrated, and the resulting orange oil was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (453 mg, 71%) as a yellow foam. LC-MS (ES) m/z=187 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:50](Cl)[CH2:51]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:50][CH3:51])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 60 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml dichloromethane were added 20 mg EDC, 13 mg DMAP and 26 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 37 mg MS (ES+): m/e=710.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.NC(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N+:3]=1[O-:14]
Reactant: NC(N)=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C

Procedure:
2-Chloro-5-trifluoromethyl-pyridine (16, 10 mmol) was dissolved in CH2Cl2 (20 mL) and UHP (Urea-hydrogen peroxide addition compound, 21 mmol) was added. The mixture was cooled to 0° C., trifluoroacetic anhydride (20 mmol) was then slowly added to the reaction mixture. It was allowed to warm to room temperature and stirred until the reaction was completed judged by TLC. The reaction was quenched with aqueous Na2SO3, stirred for 4 h, washed with saturated aqueous NaHCO3, and dried over anhydrous MgSO4. Column chromatography afforded 1.8 g of compound 17 as oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.Cl.[NH2:21][CH2:22][C:23]([NH2:25])=[O:24]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:21][CH2:22][C:23]([NH2:25])=[O:24])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCC(N)=O
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Agent: Cl
Product: NC(=O)CNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and glycinamide hydrochloride.