Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:33][C:34](O)=[O:35])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:33][C:34]([NH:20][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:35])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Reactant: NC(c1ccccc1)c1ccccc1N1CCCCC1
Product: COC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1OC

Procedure:
Prepared from α-phenyl-2-piperidino-benzylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C@@H:9]([NH2:17])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:20]([O:24][C:25]([NH:27][C@H:28]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:20]([O:24][C:25](=[O:26])[NH:27][C@H:28]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:36][CH:37]=1)[C:29](=[O:30])[NH:17][C@H:9]([C:7]1[NH:6][C:5]2[CH:18]=[CH:19][C:2]([I:1])=[CH:3][C:4]=2[N:8]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(I)ccc3[nH]2)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a solution of (S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylamine (161 mg, 0.44 mmol) in N,N-dimethylformamide (3 mL) at 0° C. was added (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid (179 mg, 0.49 mmol) (prepared as described below), N,N-diisopropylethylamine (310 μL, 1.77 mmol), N-hydroxybenzotriazole (72 mg, 0.53 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (202 mg, 0.53 mmol) and a catalytic amount of dimethyl-pyridin-4yl-amine. The mixture was stirred under an atmosphere of nitrogen with warming to room temperature over 3 hours. The reaction was poured into ice/water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 20 to 35% v/v ethyl acetate/hexanes to give {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (260 mg, 83%).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][C@H:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:36]I.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][C:21]([N:23]([CH3:36])[C@H:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CI
Reactant: CCCCCCCCCCCCOc1ccc(CC(=O)N[C@@H](CC(=O)OCC)C(=O)OCC)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(CC(=O)N(C)[C@@H](CC(=O)OCC)C(=O)OCC)cc1
Reaction time: 0.5 h

Procedure:
To the solution of diethyl N-(4-dodecyloxyphenylacetyl)aspartate (2.0 g, 4.1 m mol) and methyl iodide (0.76 ml) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% oil, 0.2 g, 4.8 m mol) under ice cooling and the resulting mixture was stirred for 30 minutes. A saturated aqueous solution of ammonium chloride (50 ml) was added to the reaction mixture and the mixture was extracted with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain crude diethyl N-(4-dodecyloxyphenylacetyl)-N-methylaspartate (3-z).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[N:10]([CH2:12][CH2:13][OH:14])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1.CO>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:15])[N:10]([CH2:12][CH2:13][O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Subsequently, to a solution of N-(2-hydroxyethyl)-N-methylcarbamic acid benzyl ester (2.82 g, 13.5 mmol) in dimethylformamide (85 ml) were added t-butyldiphenylsilyl chloride (4.21 ml, 16.2 mmol) and imidazole (1.10 g, 16.2 mmol) in an ice bath. The resulting mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, methanol was added thereto and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (9:1) as the eluant to afford N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-methyl-carbamic acid benzyl ester (5.7 g, yield 94%) as a pale yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19].C(N(CC)CC)C.O>O1CCCC1>[CH2:21]([O:20][P:18]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: CCOP(=S)(Cl)OCC
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=S)(OCC)ON=C1C=CC(=C(C#N)c2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8 g (36 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 90 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 7.5 g (39 mmol) of diethyl chlorothiophosphate to the solution, 5.4 g (54 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. The reaction mixture is gradually warmed to room temperature, and stirred overnight. The reaction mixture is poured into 100 ml of water, and extracted with ethyl acetate. The organic phase is washed with 0.1N hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by flash chromatography on silica gel with ethyl acetate—hexane (1:3) as eluent. The product is a yellow solid, with mp 66-82° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3); δ [ppm]: 1.32-1.42 (m, 6H), 4.21-4.37 (m, 4H), 6.87(Z)/6.98(E) (dd, 1H), 7.17(Z)/-7.19(E) (dd, 1H), 7.26(E)17.37(Z) (dd, 1H), 7.43-7.54 (m, 6H). 1H-NMR reveals that the product is a 56:44 mixture of Z and E isomers. The signals are tentatively assigned to Z and E isomers.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CBr)cc1
Yield: 67.5 %

Procedure:
(a) A mixture of 20 g of ethyl 2-(p-tolyloxy)-2-methylpropionate, 17.7 g of N-bromosuccinimide, 0.2 g of benzoyl peroxide and 140 ml of anhydrous carbon tetrachloride is refluxed under heating for 4 hours. After the reaction, the reaction mixture is left to stand for cooling and washed with water. The carbon tetrachloride layer is dried and then concentrated. The resulting oily product (28 g) is distilled under reduced pressure to give 18.3 g of ethyl 2-(4-bromomethylphenoxy)-2-methylpropionate, bp 146° to 148° C./1-2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:19]1(=[O:26])[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([CH:20]1[C:21](=[O:25])[CH2:22][CH2:23][CH2:24][C:19]1=[O:26])=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: Cn1nnn(-c2c(Cl)ccc(C(=O)Cl)c2Cl)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnn(-c2c(Cl)ccc(C(=O)C3C(=O)CCCC3=O)c2Cl)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.1 %

Procedure:
A dichloromethane solution of the crude 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoyl chloride (1.10 g) was added drop by drop to the solution of 1,3-cyclohexanedione (0.44 g) and triethylamine (0.43 g) in dichloromethane (8 ml) at 5° C. and the mixture was stirred at room temperature for 6 hours. After completion of the reaction it was extracted with dichloromethane (150 ml), washed with diluted hydrochloric acid and aqueous solution of sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The residue, obtained by distilling off the dichloromethane, was dissolved in acetonitrile (7 ml), added with triethylamine (0.43 g) and acetonecyanohydrin (18 mg) and stirred at room temperature for 8 hours. After the solvent was distilled off, the residue was acidified by addition of diluted hydrochloric acid and extracted with ethyl acetate (150 ml). The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective 2-[2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoyl]cyclohexan-1,3-dione (0.70 g, 51% yield from 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoic acid) was obtained. mp 138-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.[C:18](=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[C:18]([OH:20])=[O:19]
Reactant: Fc1ccc(Cl)cc1Br
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-4-chloro-1-fluorobenzene (4.31 g, 20 mmol) was added dropwise to a −78° C. solution of LDA in THF (prepared from diisopropylamine (3.38 ml, 24 mmol) and n-BuLi (1.6 M, 13.1 ml, 21 mmol)). The mixture was stirred at −78° C. for 1 h, and then was transferred slowly (˜30-60 min) via canula to a stirred −78° C. mixture of dry ice and THF (40 ml). The mixture was stirred at −78° C. for 1 h, and then was allowed to warm to rt (gas evolution). The mixture was concentrated, and was then treated with 50 ml of 1 N sodium hydroxide solution. The mixture was extracted with ethyl acetate (discarded). The aqueous layer was acidified with 1N hydrochloric acid, and then was extracted with chloroform (3×400 ml). The chloroform extract was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound. The product was contaminated with a small amount of the isomeric product 2-bromo-6-chloro-3-flurobenzoic acid. 1H NMR for title compound 3-Bromo-5-chloro-2-fluorobenzoic acid: (400 MHz, CDCl3) δ 7.93 (dd, 1H, J=2.8, 5.6 Hz), 7.79 (dd, 1H, J=2.8, 5.6 Hz) ppm.
Reaction SMILES: [Na].[CH2:2]([CH:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:3][CH3:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[CH2:2]([CH:5]1[S:9][C:8](=[O:10])[N:7]([CH2:16][CH2:15][CH2:14][CH2:13][Br:12])[C:6]1=[O:11])[CH2:3][CH3:4]
Reactant: CCCC1SC(=O)NC1=O
Reactant: BrCCCCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC1SC(=O)N(CCCCBr)C1=O
Yield: 67 %

Procedure:
The sodium salt of 5-(propyl)-2,4-thiazolidinedione (1.59 g., 0.0088 mole) in 80 ml. of dry dimethylformamide is slowly added to 1,4-dibromobutane (5.68 g., 0.026 mole) in 20 ml. of dry dimethylformamide according to the procedure of Example 1(b) affords a 67% yield of 5-(propyl)-3-(4-bromobutyl)-2,4-thiazolidinedione, b.p. 117°-120° C. at 0.02 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(C#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([O:20][C:16](=[O:19])/[CH:17]=[CH:18]/[C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Nc1ncc(Br)cc1CN1CCCCC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c(CN2CCCCC2)c1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
A solution of 5-bromo-3-piperidin-1-ylmethyl-pyridin-2-ylamine (500 mg, 1.85 mmol), tert-butyl acrylate (0.3 mL, 2.0 mmol), (i-Pr)2EtN (0.5 mL, 2.8 mmol) and P(o-tol)3 (114 mg, 0.37 mmol) in EtCN (10 mL) was de-oxygenated with argon for 30 min. Pd(OAc)2 (43 mg, 0.19 mmol) was added, and the mixture was de-oxygenated for 15 min. The mixture was heated to reflux for 18 h and then allowed to cool. The solvent was removed in vacuo. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O and satd NaCl, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, CH2Cl2 to 96:4 CH2Cl2/CH3OH) gave the title compound (350 mg, 60%) as a yellow solid: MS (ESI) m/e 318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH2:33][CH2:34][CH2:35][OH:36]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:33][CH2:34][CH2:35][OH:36])[N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCO)n2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 144 mg (0.296 mmol) 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea, 40 mg (0.65 mmol) 2-aminoethanol and 5 ml THF was stirred at r.t. for 12 h. The reaction mixture was evaporated and the residue purified by chromatography on silica (dichloromethane/ethanol 96:4). Yield 56 mg (40%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])O>CS(C)=O>[CH3:34][O:35][C:36](=[O:40])[C@H:37]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[C:4]([F:16])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1)[CH3:39]
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 24 g (0.1 mol) of 4-(5-chloro-3-fluoropyridin-2-yloxy)-phenol in 80 ml of dimethylsulfoxide is added dropwise to a stirred solution of 13.8 g (0.1 mol) of potassium carbonate in 50 ml of dimethylsulfoxide. When everything is added, the mixture is stirred for 2 hours at room temperature and then 25.8 g (0.1 mol) of (S)(-)-lactic acid-methylester tosylate is added dropwise over 30 minutes. The mixture is heated to 60° and stirred at that temperature for 20 hours, then poured onto ice/water and the organic material is extracted three times with ether. The ether-layer is washed with water and saturated salt solution, dried over magnesium sulfate, filtered and evaporated. The residue is passed for purification through a silicagel column with a hexane/ethyl acetate 3:1 solvent. After distillation of the solvent, 26 g of a clear oil of the above ester is obtained ([α]D20 =+38.8±0.5° 2% in acetone).
Reaction SMILES: Cl[Si:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH:28]1([Na])[CH:32]=[CH:31][CH:30]=[CH:29]1.C1CC=CC=1.[H-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.O>[CH:31]1([Si:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:30]=[CH:29][CH:28]=[CH:32]1
Reactant: [Na]C1C=CC=C1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)C1c2ccccc2-c2ccccc21
Agent: C1=CCC=C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C1=CC([Si](c2ccccc2)(c2ccccc2)C2c3ccccc3-c3ccccc32)C=C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
80 g (0.21 mol) of (2a) were added at 10° C. to an about 2 molar solution of cyclopentadienylsodium in tetrahydrofuran (THF), prepared from 27.8 g (0.42 mol) of freshly cracked cyclopentadiene and 16.7 g (0.42 mol) of 60% strength sodium hydride (as an oil suspension) in 200 ml of THF and the reaction mixture was stirred at room temperature for 3 hours. 300 ml of water and 400 ml of toluene were subsequently added. After phase separation, extraction with a further 250 ml of toluene and drying over magnesium sulfate, the solvents were removed and the residue was taken up in 240 ml of n-heptane. The solid was filtered off, washed with n-heptane and dried under reduced pressure. 57 g (65%) of 2b were obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11].C(OC(=O)COC)(C)C.COCC(N)=O>CC(OC)(C)C>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13]
Reactant: COC(C[C@@H]1CCCC[C@H]1N)OC
Agent: COCC(=O)OC(C)C
Agent: COCC(N)=O
Solvent: COC(C)(C)C
Product: COC(C[C@H]1CCCC[C@@H]1N)OC
Temperature: 25 °C
Reaction time: 25 h
Yield: 46.2 %

Procedure:
A dry solution of 2.1 g (11.2 mmole) trans-1-amino-2-(2,2-dimethoxyethyl)-cyclohexane and 1.38 g (10.4 mmole) methoxy acetic acid isopropyl ester in 20 ml MTBE was mixed with 200 mg immobilized lipase Novozym® 435 and shaken for 25 hours at room temperature. After this period of time the conversion was 49.5%. The (1R, 2S)-enantiomer was acylated to the methoxy acetamide, while the (1S, 2R)-enantiomer was not acylated. After removal of the enzyme by filtration, removal of the solvent using an rotary evaporator and purification by column chromatography (silica gel, eluation starting with MTSE and finally with MTBE/methanol)970 mg of pure (1S, 2R)-1-amino-2-(2,2-dimethoxyethyl)-cyclohexane (46% yield) were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[N:6]=[CH:5]2.[N:15]1[N:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:19]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[N:15]1[N:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=5)[N:8]=4)=[O:14])[CH2:25]3)[C:19]=12
Reactant: Cc1ccc2nc(C(=O)O)ncc2c1
Reactant: N[C@H]1CCN(c2nccn3cnnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2nc(C(=O)N[C@H]3CCN(c4nccn5cnnc45)C3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of 6-methylquinazoline-2-carboxylic acid (0.040 g, 0.21 mmol, 1.2 eq) and (S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine (0.49 g, 0.18 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.10 mL, 0.7 mmol, 4 eq) and HATU (0.075 g, 0.20 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide (0.028 g, 0.07 mmol, 42%). 1H NMR (400 MHz, DMSO) δ 9.62 (s, 1 H), 9.31 (t, J=3.9 Hz, 1 H), 8.08-8.00 (m, 2 H), 8.00-7.92 (m, 1 H), 7.85 (d, J=5.1 Hz, 1 H), 7.29 (d, J=5.0 Hz, 1 H), 4.82-4.70 (m, 1 H), 4.70-3.60 (br, 4 H), 2.56 (s, 3H), 2.40-2.20 (br, 2 H); MS: (ES) m/z calculated for C19H18N8O [M+H]+ 375.2, found 375.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P(Br)(Br)[Br:18]>C(OCC)C>[Br:18][CH2:9]/[CH:8]=[CH:7]/[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC/C=C/C1CCCCC1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrC/C=C/C1CCCCC1
Yield: 61 %

Procedure:
To a stirred solution of (E)-3-cyclohexyl-2-propen-1-ol (A. G. M. Barrett et al, Tetrahedron, 1996, 52, 15325), (1.47 g, 10.5 mmol) in diethyl ether (20 ml) and pyridine (1 ml) was added phosphorus tribromide (1.40 ml, 15 mmol) dropwise at room temperature under an atmosphere of nitrogen. Afler 16 h, the reaction mixture was carefully poured onto ice water (100 ml) and extracted with diethyl ether (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (20 g) column chromatography cluting with hexane:ethyl acetate (4:1) to give the title compound as a colourless oil (1.3 g, 61%).