Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C@:14]([CH2:16][OH:17])([CH3:15])[C@@H:13]3[CH2:18][CH2:19][C@@:20]4([CH3:40])[C@:25]5([CH3:39])[CH2:26][C@@H:27]([OH:38])[C@:28]67[CH2:36][O:37][C@:24]5([C@@H:29]6[CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][CH2:33]7)[CH:23]=[CH:22][C@@H:21]4[C@@:12]3([CH3:41])[CH2:11][CH2:10]2)[C@H:5]([OH:42])[C@@H:4]([O:43][C@@H:44]2[O:49][C@H:48]([CH2:50][OH:51])[C@@H:47]([OH:52])[C@H:46]([OH:53])[C@H:45]2[OH:54])[C@H:3]1[OH:55].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C@:14]([CH2:16][OH:17])([CH3:15])[C@@H:13]3[CH2:18][CH2:19][C@@:20]4([CH3:40])[C@@:25]5([CH3:39])[C:24](=[C:29]6[C@@:28]([CH2:36][OH:37])([C@H:27]([OH:38])[CH2:26]5)[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30]6)[CH:23]=[CH:22][C@@H:21]4[C@@:12]3([CH3:41])[CH2:11][CH2:10]2)[C@H:5]([OH:42])[C@@H:4]([O:43][C@@H:44]2[O:49][C@H:48]([CH2:50][OH:51])[C@@H:47]([OH:52])[C@H:46]([OH:53])[C@H:45]2[OH:54])[C@H:3]1[OH:55]
Reactant: C[C@H]1O[C@@H](O[C@H]2CC[C@@]3(C)[C@@H](CC[C@]4(C)[C@@H]3C=C[C@]35OC[C@@]6(CCC(C)(C)C[C@H]63)[C@H](O)C[C@]54C)[C@]2(C)CO)[C@H](O)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](O[C@H]2CC[C@@]3(C)[C@@H](CC[C@]4(C)[C@@H]3C=CC3=C5CC(C)(C)CC[C@]5(CO)[C@H](O)C[C@]34C)[C@]2(C)CO)[C@H](O)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O
Reaction time: 9.5 h

Procedure:
By way of example, the fully acetylated saikosaponin d can be obtained by adding 10 to 20 ml of acetic anhydride to a solution of saikosaponin d in 10 to 20 ml/g of pyridine and allowing the mixture to stand at 10° C. to 50° C. for 3 to 16 hours. When this reaction mixture is stirred with a 1 to 40% (w/w) aqueous solution of ferric chloride at 10° C. to 40° C. for 1 to 10 hours for cleavage of the ether ring, there is obtained the acetylated saikosaponin b2 in which only the hydroxy group in the 28 position is free. This product is subjected to the above-described phosphorylation reaction with DPC and, then, to hydrolysis of the acetyl groups under alkaline conditions (pH 9-14, preferably pH 10-13), whereby the salt of saikosaponin b2 -28-(dihydrogen phosphate) is obtained. In the same manner as above, a salt of saikosaponin b1 -28-(dihydrogen phosphate) can be obtained from saikosaponin a, and a salt of saikosaponin h-28-(dihydrogen phosphate) from saikosaponin c.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([CH3:10])[CH:8]=[O:9]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([CH3:10])[CH2:8][OH:9]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde (2.0 g, 6.68 mmol) in ethanol (30 mL) is added to NaBH, (0.25 g, 6.6 mmol) in portions at 0° C. The reaction is kept at 0° C. for 15 minutes and warmed up to room temperature for 2 hours. The reaction is quenched using water, extracted with ethyl acetate, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate gave the title compound (2.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:37])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH3:37])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C

Procedure:
To 0.123 g (0.516 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.163 g (0.540 mmol) of the above prepared 3-chloromethyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine, dissolved in 4.7 ml of abs. acetonitrile, was added 0.184 g of Cs2CO3 (0.565 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2) yielded 0.243 g of pure title compound as colorless oil.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:8]([NH:17][C:18]([C:20]2[N:21]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=3)[N:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=2)=[O:19])=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:6])([CH3:3])[CH3:2].[OH-].[K+].CC([O-])(C)C.[K+].Cl[CH2:45][O:46][CH3:47]>C1COCC1.O.CCOC(C)=O>[CH:1]([NH:4][C:5]([C:7]1[C:8]([NH:17][C:18]([C:20]2[N:21]([C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=3)[N:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=2)=[O:19])=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:45][O:46][CH3:47])[N:13]=[CH:12]2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(Cl)cc2cn[nH]c12
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1ncc2cc(Cl)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-1H-indazole-7-carboxylic acid isopropylamide (1.00 g, 1.90 mmol), KOH (310 mgs, 5.70 mmol) and t-BuOK (6.4 mg, 0.02 mmol) in THF (5 mL) was treated dropwise with chloro-methoxy-methane (0.39 mL, 5.1 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h. AcOEt and water was added. The phases were separated. The aqueous layer was extracted with AcOEt. The organic layers were washed with water, combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by reverse phase HPLC affords the title product as a colorless solid. M.p. 180-182° C., LC/MS: 570/572 (M+H)+, 592/594 (M+Na)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>CN(C=O)C.C(OCC)(=O)C>[Cl:42][CH2:41][CH2:40][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:32])[CH:14]=3)[C:19]2=[O:23])=[CH:30][CH:29]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(O)cc3)ccc2c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1
Temperature: 50 °C
Reaction time: 40 h

Procedure:
To a solution of the product of step i) (500 mg) in DMF (10 mL) was added potassium carbonate (820 mg) and 1-bromo-2-chloroethane (0.2 mL) and the reaction was heated at 50° C. for 22 hours. Additional 1-bromo-2-chloroethane (0.3 mL) and potassium carbonate (820 mg) were added and heating continued for 40 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was purified (SiO2, ethyl acetate:isohexane (6:4)) to yield the sub-titled compound (280 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.Br[C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:21]#[N:22])=[C:18]([F:25])[CH:17]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].[Pd].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:21]#[N:22])=[C:18]([F:25])[CH:17]=1
Reactant: c1ccc2ocnc2c1
Reactant: N#CCc1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of benzoxazole (153 mg, 1.3 mmol) in 5 mL THF at −78° C., was added n-Butyllithium (640 μL, 2.5M in hexanes, 1.6 mmol). The reaction mixture was stirred for 15 min at −78° C. and ZnCl2 (3.9 mL, 1.0M solution in Et2O, 3.9 mmol) was added via a syringe. The reaction was then warmed to 0° C. for 1 h and a solution of 4-bromo-2-fluoro benzyl cyanide (214 mg, 1.0 mmol) in THF (2 mL) was added, along with Pd (a fine suspension prepared as follows: 200 μL n-Butyllithium, 2.5M in hexanes added to 144 mg PdCl2(PPh3)2 in 5 mL of THF). The reaction mixture was then stirred at reflux overnight, quenched with sat. NaHCO3 (50 mL) and diluted with EtOAc (300 mL). The resulting organic layer was washed with H2O (1×50 mL), dried (MgSO4) and concentrated in vacuo. The residue purified by flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-fluorophenyl]acetonitrile as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 8.14 (q, 1H), 8.2 (q, 1H), 7.82 (m, 1H), 7.63 (m, 2H), 7.42 (m, 2H), 3.85 (s, 2H). MS (ESI) 253 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[N:7]([CH3:16])[CH2:6]2.O.O.Cl[Sn]Cl.C(Cl)Cl.[OH-].[Na+]>C(O)C.O>[NH2:12][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH3:16])[C:8]2=[O:15])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(=O)N(C)C2
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(cc1N)C(=O)N(C)C2
Temperature: 65 °C
Yield: 97.3 %

Procedure:
To crude 5-methoxy-2-methyl-6-nitroisoindolin-1-one (121 mg, 0.54 mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl2.2H2O (487 mg, 2.16 mmol) and the mixture was heated to 65° C. for 24 h. DCM (10 mL) and 2M NaOH(aq) (10 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give impure 6-amino-5-methoxy-2-methylisoindolin-1-one (101 mg, 97%) as an off-white solid. The crude material was used directly in the next reaction without any further purification. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=193 at 2.00 min.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:15][CH2:16][CH:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19]>FC(F)(F)C(O)=O>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:15][CH2:16][CH:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]([N:20]2[CH2:27][CH2:26][CH2:25][C@H:21]2[C:22]([OH:24])=[O:23])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C(CS)Cc1ccccc1
Reactant: OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CSC(c1ccccc1)c1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Diphenylmethanol (0.92 g) and 1-(3-mercapto-2-benzylpropanoyl)-L-proline (1.5 g) are dissolved in trifluoroacetic acid (10 ml) and the solution is kept at room temperature for 30 minutes. The excess trifluoroacetic acid is removed in vacuo to yield 1-[3-[(diphenylmethyl)thio]-2-benzylpropanoyl]-L-proline.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:30])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:25][CH:24]([CH2:26][CH3:27])[O:23][CH:22](O)[CH2:21]3)[C:11]=2[Cl:29])[CH:5]=[N:4]1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:30])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:20]3[CH2:21][CH2:22][O:23][CH:24]([CH2:26][CH3:27])[CH2:25]3)[C:11]=2[Cl:29])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCC1CN(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(CC)c3O)c2Cl)CC(O)O1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCC1CN(c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(CC)c3O)c2Cl)CCO1
Reaction time: 2 h

Procedure:
A solution of 500 mg (1.09 mmol) of 1-ethyl-4-(2-chloro-3-(6-ethyl-2-hydroxymorpholin-4-yl)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 3 mL of trifluoroacetic acid was treated with 1 mL of triethylsilane at ambient temperature and stirred vigorously for 2 hours. The solvent was removed by evaporation under reduced pressure and the orange residue obtained was partitioned between dichloromethane and water. The organic solution was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The solid residue was recrystallized from ethanol to obtain 210 mg (44 percent of theory) of the title compound as light orange-brown crystals.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)(=[O:32])=[O:33])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NS(=O)(=O)c2ccc(C)cc2)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.361 g (2.1 mmol) of 4-methylbenzenesulfonamide. MS (m/z, ES−): 476.63 (M−1, 100%).
Reaction SMILES: [C:1]([O:21][CH3:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:13].[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:27]([O:13][C@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:21][CH3:22])=[O:20])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:29]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:28]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC[C@H](C/C=C\CCCCCCCC(=O)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 148.6 %

Procedure:
To a solution of methyl ricinoleate (8.0 g, 32 mmol) in anhydrous pyridine (90 mL) and anhydrous THF (45 mL) was added t-butylchlorodimethyl silane (8.5 mL, 33.3 mmol) and silver nitrate (5.65 g, 33.3 mmol). The solution was stirred at room temperature for 90 minutes under nitrogen. The solution was filtered through celite and the filter cake was rinsed with THF (400 mL). The filtrate was concentrated in vacuo and the residue was dissolved in dichloromethane (300 mL) and washed with 5% HCl (150 mL). The aqueous layer was separated and washed with dichloromethane (2×200 mL). The combined dichloromethane extracts were washed with brine (350 mL), dried on magnesium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (gradient: 100% hexanes to 10% ethyl acetate in hexanes) to afford the title compound as a colourless oil (13.1 g, 93%).
Reaction SMILES: C[C@H]1[C@H](NC2N=CC(C(F)(F)F)=CN=2)CCCN1C(OC(C)(C)C)=O.[CH3:26][C@H:27]1[C@H:32]([NH:33][C:34]2[CH:39]=[N:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=2)[CH2:31][CH2:30][CH2:29][N:28]1C(OC(C)(C)C)=O>>[CH3:26][C@H:27]1[C@H:32]([NH:33][C:34]2[CH:39]=[N:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][N:35]=2)[CH2:31][CH2:30][CH2:29][NH:28]1
Reactant: C[C@H]1[C@H](Nc2cnc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Agent: C[C@H]1[C@H](Nc2ncc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Product: C[C@@H]1NCCC[C@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared analogous to example 69 Step B substituting the title compound of Step A example 69 with the title compound of Step A. MS (ESI) mass calcd. for C11H15F3N4, 260.2; m/z found 261 [M+H]+.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.Br([O-])(=O)=O.[K+:35].[OH-].[K+].CCCCCCCC/C=C\CCCCCCCC(OCC(O)[C@H]1OC[C@H](O)[C@H]1O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([O-:10])(=[O:9])[CH:7]=[CH2:8].[K+:35]
Reactant: C=CC(=O)O
Agent: C=CC(N)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Solvent: O
Product: C=CC(=O)[O-]
Reaction time: 8 h

Procedure:
The copolymer may be manufactured as follows: a water phase containing 199.1 g of acrylamide, 84.5 g of acrylic acid, 3.0 g of ethylenediaminetetraacetic acid, 0.2 g of potassium bromate, 60.3 g of potassium hydroxide and 342 g of water is homogenized with an oil phase containing 240 g of oil, 20 g of sorbitan monooleate, 0.2 g of 2,2'-azobis-(isobutyronitrile). The emulsion is then transferred to a suitable reaction vessel with stirring and is sparged with nitrogen. Polymerization is initiated and sustained by continuously adding a solution of sodium metabisulfite throughout the exotherm. The cooling is provided to maintain the temperature of the system between 35° C.-45° C. The polymerization is completed in about 6-10 hours to give an emulsion product of acrylamide/potassium acrylate copolymer. To produce a self-inverting product, 24 g of a breaker system composed of a 1.75:1 blend of the reaction product of nonylphenol with 6 moles of ethylene oxide and the reaction product of dinonylphenol with 24 moles of ethylene oxide is added.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:25])[C:4]([C:10](=[O:24])[NH:11][CH2:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH:26]1[CH2:29][CH2:28][CH2:27]1>>[CH3:19][N:18]1[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=[C:14]1[CH2:13][CH2:12][NH:11][C:10]([C:4]1[N:3]([CH3:25])[C:2]([Cl:1])=[N:6][C:5]=1[C:7]([N:26]1[CH2:29][CH2:28][CH2:27]1)=[O:9])=[O:24]
Reactant: Cn1c(Cl)nc(C(=O)O)c1C(=O)NCCc1nc2ccccc2n1C
Reactant: C1CNC1
Product: Cn1c(Cl)nc(C(=O)N2CCC2)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 2-chloro-1-methyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-imidazole-4-carboxylic acid (30 mg, 82.9 μmol) and azetidine (14.2 mg, 16.9 μl, 249 μmol) according to the method described in example 7, step 5 as white waxy solid (17.5 mg, 41.5 μmol, 50.0%). MS: M=401.2 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]([CH3:22])([CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CO.O.[OH-].[Li+]>O>[CH3:21][C:4]([CH3:22])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]([OH:23])=[O:2]
Reactant: CCCCCCCC/C=C\CCCCCCC(C)(C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCC(C)(C)C(=O)O
Reaction time: 18 h

Procedure:
The material from Example 67 was treated with methyl alcohol (300 ml), lithium hydroxide monohydrate (6.3 g) and water (100 ml) and stirred for about 18 hrs. at room temperature. After warming on a hot plate for 6 hrs. and allowing to stir ovrnight at room temperature, the methyl alcohol was removed on a rotary evaporator and the aqueous residue acidified with 1N hydrochloric acid to pH 2. The product was extracted into ethyl acetate (2×100 ml), dried over sodium sulfate, filtered and stripped of solvent to yield an oil. The title compound was purified by chromatography on silica gel.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[Cl:10][C:11]1[N:16]=[C:15]([NH2:17])[CH:14]=[N:13][CH:12]=1.BrC1N=CC(N)=NC=1Cl>C(Cl)(Cl)Cl>[Br:1][C:14]1[C:15]([NH2:17])=[N:16][C:11]([Cl:10])=[CH:12][N:13]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Nc1cncc(Cl)n1
Agent: Nc1cnc(Br)c(Cl)n1
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)cnc1Br

Procedure:
N-bromosuccinamide (6.9 g) was added portionwise over 0.5 h to a stirred solution of 6-chloro-2-pyrazinamine (5.0 g) in chloroform (200 mL) heated under reflux. After the addition was complete the reaction mixture was allowed to cool, washed with water and evaporated to give a 3:1 mixture of 5-bromo-6-chloro-2-pyrazinamine and the subtitle compound which were separated by silica gel chromatography eluting with dichloromethane. Yield 2.0 g. Used directly.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(OCC)(=O)C>[N:13]1([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCc2ccc(N3CCOCC3)cc21
Yield: 58.4 %

Procedure:
A solution of 7-bromo-3,4-dihydro-2H-naphthalen-1-one (600 mg), morpholine (1.16 g), tripotassium phosphate (850 mg), tris(dibenzylideneacetone)dipalladium (0) (24.4 mg) and 2-(di-tert-butylphosphino)biphenyl (15.9 mg) in toluene (5.0 mL) was stirred in a nitrogen atmosphere at 100° C. overnight. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain 360 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH:4]([S:8][C:9]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][N:10]=1)[C:5]([OH:7])=O.Cl.[NH2:22][CH2:23][C:24]#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.O>[C:23]([CH2:24][NH:25][C:5](=[O:7])[CH:4]([S:8][C:9]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][N:10]=1)[CH2:3][CH:2]([CH3:1])[CH3:20])#[N:22]
Reactant: N#CCN
Reactant: CC(C)CC(Sc1nnc(-c2ccccc2)[nH]1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(Sc1nnc(-c2ccccc2)[nH]1)C(=O)NCC#N
Reaction time: 0.01 h

Procedure:
To a solution of the crude 4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanoic acid in DMF (10 mL) was added aminoacetonitrile hydrochloride (427 mg, 4.62 mmoles) and HATU (1.76 g, 4.62 mmoles). After stirring for 30 seconds, triethylamine (1.3 mL, 9.24 mmoles) was added in one portion. The reaction was stirred overnight, diluted with ethyl acetate and water. The organic phase was separated and washed twice with 1.2 N hydrochloric acid, brine and dried over magnesium sulfate. After concentration under reduced pressure, N-(cyanomethyl)-4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanamide was obtained. MS (−APCI): 328.2 [M−1]−.