Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[C:6]([C:17]([OH:19])=O)[CH:5]=1.[NH2:22][C@@H:23]([CH3:40])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:17]([C:6]3[CH:5]=[C:4]([CH2:3][C:2]([OH:1])([CH3:21])[CH3:20])[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[N:7]=3)=[O:19])[CH3:40])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)(O)Cc1cc(C(=O)O)nn1COCC[Si](C)(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(CC(C)(C)O)n(COCC[Si](C)(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 5-(2-hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazole-3-carboxylic acid (1.59 mmol, 500 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.59 mmol, 442 mg). The product was purified by flash-chromatography. Yield 295 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.13 (s, 9H), 0.68 (t, 2H), 1.06 (s, 3H), 1.08 (s, 3H), 1.20 (d, 3H), 2.61 (s, 2H), 3.40 (t, 2H), 4.23-4.42 (m, 3H), 4.51 (s, 1H), 5.54 (d, 1H), 5.68 (d, 1H), 6.72 (s, 1H), 7.01 (d, 1H), 7.84-7.87 (m, 2H), 7.96 (s, 1H), 8.40 (d, 1H). LC-MS: [M+1]=575.01.
Reaction SMILES: [C:1]([OH:15])(=[O:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=C[CH:19]=[CH:18][CH:17]=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:19]([O:14][C:1](=[O:15])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:18]=[CH2:17]
Reactant: c1ccncc1
Reactant: CCCCCCC=CC=C/C=C/C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCOC(=O)/C=C/C=CC=CCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.2 g of 3,7,11-trimethyl-2-cis/trans, 4-cis/trans, 10-cis/trans-tridecatrienoic acid are dissolved in 65 ml of absolute benzene and 3.5 ml of pyridine and then treated at a temperature between 5° C and 10° C with 3.4 ml of thionyl chloride (dropping time ca 15 minutes). The mixture is subsequently stirred for 1 hour at room temperature, then the liquid is decanted off and the residue is washed out with benzene. The solution is evaporated to dryness under anhydrous conditions. The residue is dissolved in 20 ml of absolute benzene and added dropwise at a temperature between 5° C and 10° C to a solution of 3.6 ml of allyl alcohol and 3.5 ml of pyridine in 50 ml of benzene (dropping time ca 30 minutes). After stirring overnight at room temperature, the solution is diluted with ether and washed with 1-N aqueous hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and finally with sodium chloride solution. After drying, the ether phase is evaporated. The crude product is chromatographed on the 30-fold amount of Kieselgel (eluant: hexane/ether 19:1 parts by volume). 3,7,11-Trimethyl-2-cis/trans, 4-cis/trans, 10-cis/trans-tridecatrienoic acid allyl ester is obtained as a colorless oil of boiling point 120° C/0.05 mmHg (bulb-tube); nD25 = 1.5026.
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:14])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25]>CN(C=O)C.O>[CH3:25][CH:24]([CH3:26])[C:23](=[O:27])[CH2:22][NH:14][C:3]([CH3:2])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH3:4]
Reactant: CC(C)(N)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)CNC(C)(C)c1cccc([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 1-methyl-1-(3-nitro-phenyl)-ethylamine hydrochloride (600 mg, 2.8 mmol) in DMF (8 mL) was added anhydrous potassium carbonate (1.5 g, 11 mmol) and 1-bromo-3-methyl-2-butanone (prepared according to Organic Syntheses, Collective Volume 6, page 193) (0.45 mL, 3.62 mmol). The mixture was stirred for 3 h then diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried and concentrated to dryness under reduced pressure to afford 3-methyl-1-[1-methyl-1-(3-nitro-phenyl)-ethylamino]-butan-2-one (650 mg, 89%) as an oil which was used immediately in the following step.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C[N+](C)(C)C.[OH-]>[CH3:13][S:14]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=[O:16])=[O:15]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: C=Cc1ccc(OS(C)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Approximately 100 gs (6.17×10-1 moles) of 4-acetoxystyrene was added slowly to a cooled stirred solution (480 mL) of 25% TMAH (the temperature was maintained below 25° C. during the addition.) After about 1/2 to 1 hour of stirring, a clear, yellowish solution was obtained. This solution was cooled to 5° C. and the methanesulfonyl chloride 79.5 gs (0.75×10-1 moles) was added with stirring while the temperature was kept below 15° C through cooling with an ice bath. The reaction mixture was stirred for 1/2 hour until neutral pH was observed in the solution. After this time the resulting crystals were filtered-off, washed with distilled water, and sucked dry. The crystals were dissolved in a minimal amount of methylene chloride and recrystallized by addition of hexane. In this way 76 gs (62% yield) of white crystals were recovered. Analysis of the product indicated:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]1[CH2:12][O:11][CH:10]=[CH:9][CH2:8]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.C1COCC1>[O:11]1[CH2:12][CH2:7][CH2:8][CH2:9][CH:10]1[O:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: C1=COCCC1
Reactant: O=C(O)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 3-hydroxypropanoic acid (7.2 g, 80 mmol, TCI, TOKYO KASEI) and DHP (13.4 g, 160 mmol, Alfa) in dichloromethane (100 mL) and THF (100 mL) was added PPTS (2 g, 8 mmol, Aldrich) in portions. The reaction mixture was stirred at rt overnight, and was quenched with 50 mL of saturated NaHCO3 aqueous solution. The resulted mixture was extracted with dichloromethane (50 mL×5). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:1 (v/v) petroleum ether/EtOAc) to give colorless oil (7.8 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)[S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:4][C:3]=1[C:20]([F:23])([F:21])[F:22]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1c(NCc2ccc(F)c(C(F)(F)F)c2)nc2ccccc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)nc2ccccc21
Temperature: 100 °C

Procedure:
To (4-fluoro-3-trifluoromethyl-benzyl)-(1-methyl-1H-benzimidazol-2-yl)-amine (195 mg, 0.6 mmol) in anhydrous pyridine (3 mL) at room temperature was added benzenesulfonyl chloride (193 mg, 1.1 mmol). The resulting mixture was heated to 100° C. in a microwave reactor for 1 h; then diluted with EtOAc, washed with 1 N HCl, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield the title compound. MS 464 (M+1)+
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([NH2:19])[CH3:18].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:19][CH2:17][CH3:18]
Reactant: CCN
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
3,5-Bis-trifluoromethylbenzaldehyde (3.00 g) is dissolved in 1,2-dichloroethane (50 ml), and thereto are added 70% aqueous ethylamine solution (0.80 ml) and acetic acid (2.1 ml), followed by an addition of triacetoxy-sodium borohydride (13.1 μg) at room temperature over 1 hour with stirring. The mixture is stirred at room temperature for additional 30 minutes, and to the reaction mixture is then added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane ethyl acetate=4:1) to give (3,5-bis-trifluoromethyl-benzyl)-ethyl-amine (1.52 g). MS (m/z): 272 [M+H]+
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Br)(Br)(Br)(Br)[Br:24]>>[Br:24][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: BrP(Br)(Br)(Br)Br
Reactant: CCOC(=O)C(O)CCc1ccc(-c2ccccc2Cl)cc1
Product: CCOC(=O)C(Br)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
To 15.4 g. (0.0476 moles) of ethyl α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyrate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-γ-(2'-chloro-4-biphenylyl)butyrate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cncc(Br)c1
Solvent: C1CCOC1
Product: O=C(Nc1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 5-bromopyridin-3-amine (0.3 g, 1.734 mmol) in THF (8.67 ml) was added TEA (0.363 ml, 2.60 mmol), and then benzoyl chloride (0.292 g, 2.081 mmol) was added to the mixture at 0° C. After stirred for 2 hours at room temperature, the reaction mixture was quenched with saturated aq. NaHCO3 (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=10:1) to give N-(5-bromopyridin-3-yl)benzamide (0.435 g, 91%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.48 (2H, t, J=7.6 Hz), 7.58 (1H, t, J=7.4 Hz), 7.85-7.88 (2H, m), 8.38 (1H, brs), 8.40 (1H, d, J=1.6 Hz), 8.56-8.58 (2H, m).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=3)[CH:19]=[C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:13][CH:14]=2)O1.C(OO)(C)=[O:38]>C1COCC1>[OH:38][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=2)[CH:19]=[C:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]2)=[N:13][CH:14]=1
Reactant: CC(=O)OO
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(B4OC(C)(C)C(C)(C)O4)cn3)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (3.45 g, 7 mmol) in THF (15 mL) was added AcOOH (4.6 mL, 60.67 mmol) at 0° C. The temperature was allowed to warm to RT and the reaction was stirred for 3 h. The reaction was quenched with Na2SO3 solution at 0° C. and the pH of the solution was adjusted to 7-7.5. Then the mixture was extracted with ethyl acetate and the organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (1:3 acetone:hexane) to give the title compound (2.02 g, 75%). 1H NMR (500 MHz, DMSO-d6): δ 9.67 (s, 1H), 7.72 (s, 1H), 7.28 (m, 2H), 6.98 (d, J=7.2 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.85 (d, J=7.5 Hz), 6.83 (s, 1H), 6.35 (s, 1H), 3.41 (m, 2H), 3.31 (m, 2H), 2.38 (m, 2H), 2.27 (m, 2H), 1.41 (s, 9H); m/z (383.1, M+ H+).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]([N:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]2[CH3:31])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:34][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([N:20]([C@H:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]([C:8](=[O:9])[C:7]3[CH:32]=[CH:33][C:4]([C:1]([OH:3])([CH3:34])[CH3:2])=[CH:5][CH:6]=3)[C@@H:11]([CH3:31])[CH2:12]2)[C:21](=[O:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(C)(C)O)cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-{1-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (2S,4R)-N-[1-(4-acetyl-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-acetamide. (2S,4R)-N-[1-(4-Acetyl-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-acetamide (112 mg, 124 mmol) was dissolved in THF (5 mL) and cooled to 0° C. Methyl magnesium bromide (1.4 M in ether, 2 mL, 2.4 mmol) was added and the mixture stirred at 0° C. for 2 h. The reaction was warmed to rt and stirred an additional 2 h. The reaction was poured into saturated aqueous ammonium chloride. The phases were separated and the aqueous was extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude alcohol was purified by silica gel chromatography to afford pure product (20 mg, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:32][CH2:31][CH2:30][O:29][C:25]2[C:24]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[C:23]([NH:22][S:19]([C:16]3[CH:15]=[CH:14][C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:18][CH:17]=3)(=[O:20])=[O:21])[N:27]([CH3:28])[N:26]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(OCCO)c(-c2ccc(Cl)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: Clc1ncc(Br)cn1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc(Cl)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (21 mg) of 5-bromo-2-chloropyrimidine was used and 4-(tert-butyl)-N-[4-(4-chlorophenyl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]benzenesulfonamide (Example 19) (30 mg) was used in place of 4-(tert-butyl)-N-(3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (3 mg).
Reaction SMILES: C(OC(=O)[N:7]([CH2:23][CH2:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:10]=1)(C)(C)C.C(OC(=O)N(CCNC1C=CC=CC=1N)CC1C=CC=C(C(N2CCCCC2)=O)C=1)(C)(C)C.CCN(CC)CC.CS(Cl)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl.O>[N:17]1([C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][NH:7][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(CCNc1ccccc1NS(C)(=O)=O)Cc1cccc(C(=O)N2CCCCC2)c1
Agent: CC(C)(C)OC(=O)N(CCNc1ccccc1N)Cc1cccc(C(=O)N2CCCCC2)c1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 51 %

Procedure:
[2-(2-Methanesulfonylamino-phenylamino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester. To a solution of [2-(2-amino-phenylamino)-ethyl]-[3-(piperidine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester (Example 13, step B; 0.10 g, 0.22 mmol) in CH2Cl2 (4 mL) was added Et3N (0.033 g, 0.33 mmol) and methanesulfonyl chloride (0.028 g, 0.24 mmol), and the resulting mixture was stirred at 25° C. for 17 h. The reaction mixture was treated with satd NH4Cl (10 mL), H2O (10 mL) and CH2Cl2 (20 mL), and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (30% acetone/hexanes) to provide the desired product (0.060 g, 51%). MS (ESI): mass calculated for C27H38N4O5S, 530.26. m/z found, 531.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH:14]1([C:20](OC)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:20](=[O:21])[CH2:1][C:2]#[N:3])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC#N
Reactant: COC(=O)C1CCCCC1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC1
Reaction time: 0.08 h

Procedure:
A solution of 0.53 mL (10 mmol) of MeCN in 5 ml of THF was cooled in −78° C. bath and 12 mL of 1M LiN(TMS)2 was added. After 5 min, 0.75 mL (5.2 mmol) of methyl cyclohexane carboxylate was added. The cold bath was removed after 1 hr and stirring was continued for another 1 hr. The reaction was acidified with 1.2 N HCl and extracted with ether. The ether layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-50% EtOAc-hexane to furnish the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[C:4]=1[C:5](OC)=[O:6].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>O1CCCC1.CN(C=O)C>[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:6])[N:15]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)[CH2:2]2)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1c(C#N)cccc1CBr
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cccc(C#N)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 6C (300 mg) in tetrahydrofuran (2 mL) and N,N′-dimethylformamide (2 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (320 mg,) in N,N′-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) at −40° C. The solution was warmed to ambient temperature over 2 hours, and stirred for 16 hours. The solvent was removed, and the concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 80% ethyl acetate in hexanes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[N:9]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:39][C@H:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH3:51])[CH2:41][C:42]([OH:44])=[O:43]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([NH:39][C@H:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[CH3:51])[CH2:41][C:42]([OH:44])=[O:43])=[O:16])=[N:9]1
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Reactant: O=C(O)c1cc(O)n(-c2ccccc2F)n1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(O)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
0.45 mmol of 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid were dissolved in 5 ml of DMF, 0.54 mmol of TOTU and 1.125 mmol of NEM were added, and the mixture was stirred for 5 min at room temperature. Then 0.495 mmol of (S)-3-amino-3-o-tolyl-propionic acid were added and the mixture stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue subjected to preparative HPLC to give the title compound in a yield of 28%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][N:10]([C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24])[CH2:11][CH2:12][C:13]=2[CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c([nH]1)CNCC2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c([nH]1)CN(C(=O)OCC(Cl)(Cl)Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2-ethoxycarbonyl-4,5,6,7-tetrahydro-6-azaindole from Example 2 (8 g, 0.041 mole) in dichloromethane (200 ml) and triethylamine (4.15 g, 0.041 mole) was cooled to 0° C. and treated dropwise over 30 minutes with a solution of 2,2,2-trichloroethyl chloroformate (8.69 g, 0.041 mole) in dichloromethane (50 ml) and stirred subsequently for 30 minutes at room temperature. The mixture was quenched with water (50 ml), the organic layer separated, washed with water (50 ml), dried over sodium sulphate and evaporated to give a yellow oil which was chromatographed on silica gel (150 g) eluting with chloroform and chloroform:methanol (99:1) to give the expected pure product as a colourless solid (13.49 g, 89%), m.p. 126.5°-127° C. (from ether/hexane). Found: C, 42.24; H, 4.09; N, 7.54. C13H15Cl3N2O4 requires C, 42,24; H, 4.09; N, 7.58%.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:4]([CH2:5][CH2:6][C@@H:7]2[C:10]([NH:12][NH:13][C:14]([CH:16]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[O:15])=[O:11])[N:3]1[O:27][S:28]([OH:31])(=[O:30])=[O:29].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:18]1[CH2:17][CH:16]([C:14]([NH:13][NH:12][C:10]([C@H:7]2[CH2:6][CH2:5][C@H:4]3[CH2:9][N:8]2[C:2](=[O:1])[N:3]3[O:27][S:28]([OH:31])(=[O:30])=[O:29])=[O:11])=[O:15])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)NNC(=O)[C@H]2CC[C@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OS(=O)(=O)O)C1CNC1
Reaction time: 1 h

Procedure:
To a solution tert-butyl 3-[(2-{[(2R,5S)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]azetidine-1-carboxylate 262 (0.18 g, 0.39 mmol) in DCM (18 mL) was added trifluoroacetic acid (1.45 mL, 18.79 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with a mixture of MeOH:ether (1:5, 6×) and the white solid was collected by centrifugation to give (2R,5S)—N′-(azetidin-3-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide Compound 112 (Table 2) (0.04 g, 28%) as a white solid.