Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].FC(F)(F)C1C=CC=CC=1O[C@H]1CCNC1.[OH:18][C@@H:19]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1O>>[ClH:1].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[O:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: Oc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Agent: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Product: Fc1ccc(Br)c(O[C@H]2CCNC2)c1

Procedure:
The title compound was prepared in the same manner as described for (3S)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine hydrochloride from tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate and 2-bromo-5-fluorophenol. 1H NMR (300 MHz, DMSO-d6): δ 7.62 (m, 1H), 7.19 (m, 1H), 6.84 (m, 1H), 5.22 (s, 1H), 3.53 (s, 1H), 3.32 (m, 3H), 2.14 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])O1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]2[C:3](=[C:4]([NH2:5])[N:22]=[C:21]3[C:20]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:6]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: COc1ccc(Br)c(C#N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)c(N)nc1ccccc12
Yield: 68 %

Procedure:
2-Bromo-5-methoxybenzonitrile (1.32 g, 6.23 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.36 g, 6.23 mmol), bis(triphenylphosphine)palladiumdichloride (0.437 g, 0.623 mmol) and potassium phosphate monohydrate (4.30 g, 18.68 mmol) were added to toluene (30 mL) and water (3 mL). The reaction mixture was degassed with bubbled nitrogen gas for 30 minutes before being refluxed under nitrogen for 15 h. After cooling, the reaction mixture was filtered through Celite® and the organic layer was extracted with ethyl acetate. After removal of the solvents, the crude material was triturated with 40 mL of DCM followed by 50 mL of hexanes to give 8-methoxyphenanthridin-6-amine (0.95 g, 68%) as a light yellow solid. The product was confirmed by GC/MS and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.C([O-])(=O)C.[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(CN(O)C(=O)CCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 44 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 1.0 eq of succinic anhydride in dioxane/water (2:1) in the presence of sodium acetate (2.5 eq). The reaction mixture is diluted with ethyl acetate and is washed with dilute aqueous HCl and then with water. The crude product is purified by recrystallization from methylene chloride. The compound is dissolved in a minimal amount of methanol, diluted with water and lyophylized to give pure 4-[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]methyl]hydroxyamino]--4-oxo-butanoic acid (44%); mp 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[CH:15][C:14]=2[CH3:24])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].[CH3:25][C:26]([CH3:28])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]3[CH2:21][O:22][C:26]([CH3:28])([CH3:25])[O:23]3)=[CH:15][C:14]=2[CH3:24])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: CC(C)=O
Reactant: Cc1cc(CC(O)CO)ccc1OCCNc1ncnc(C)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(CC2COC(C)(C)O2)ccc1OCCNc1ncnc(C)c1Cl

Procedure:
6.0 g of 5-chloro-4-{2-[4-(2,3-dihydroxypropyl)-2-methylphenoxy]ethylamino}-6-methylpyrimidine and 50 ml of acetone were dissolved in 200 ml of toluene and a small amount of p-toluenesulfonic acid was added to the solution. The mixture was then heated under reflux for 6 hours. At the end of this time, the reaction mixture was adjusted to weakly alkaline by the addition of a dilute aqueous solution of sodium hydroxide. Then the reaction mixture was washed with water and dried over anhydrous sodium sulfate. Toluene was removed by distillation under reduced pressure. The oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate) to isolate the product and give 4.8 g of the title compound as a pale yellow oily liquid, n25.0 =1.5516.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:49]CCCl>>[Cl:49][C:30]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1ccc(NCc2ccc(Cl)cc2)cc1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a stirred solution of (4-amino-phenyl)-(4-phenyl-piperazin-1-yl)-methanone (200 mg, 0.71 mmol) in 1,2-dichloroethane (4 ml) at 0° C. was added 3-chlorobenzaldehyde (99.7 mg, 0.71 mmol). Sodium triacetoxy borohydride (210 mg, 0.99 mmol) and acetic acid (40.6 μl, 0.71 mmol) were added and the reaction was stirred at room temperature under nitrogen overnight. The reaction was quenched with the addition of sodium hydroxide (aq.) (pH8) and extracted with diethyl ether (3×20 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound as a yellow solid (72 mg, 25% yield). HPLC retention time 7.5 min. Mass spectrum (ES+) m/z 406 (M+H).
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[C:16]2[N:12]([C:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Cl)[CH:26]=3)=[C:14]([CH2:22]C)[C:15]=2[C:17](=[O:21])[C:18]([NH2:20])=[O:19])[CH:11]=[CH:10][CH:9]=1)([O:3][CH2:4][CH3:5])=[O:2]>CCOC(C)=O.CCCCCC>[CH2:24]([C:13]1[N:12]2[C:16]([C:8]([O:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:9][CH:10]=[CH:11]2)=[C:15]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])[C:14]=1[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COc1cccn2c(Cc3cccc(Cl)c3)c(CC)c(C(=O)C(N)=O)c12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccn2c(Cc3ccccc3)c(C)c(C(=O)C(N)=O)c12
Yield: 73 %

Procedure:
(8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2-ethylindolizin-1-yl)glyoxylamide 37h. Mp, 172-175° C. (AcOEt-hexane). 73% Yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12]Br.N>CC(O)=O>[CH3:1][N:2]1[C:6]2[C:7]([Br:12])=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: BrBr
Reactant: Cn1cnc2ccc(N)cc21
Agent: N
Solvent: CC(=O)O
Product: Cn1cnc2ccc(N)c(Br)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-5-aminobenzimidazole (0.27 g, 1.8 mmol) in 10 ml of AcOH was added Br2 (0.10 ml). The reaction mixture was stirred for 1 h at 25° C. and concentrated in vacuo, yielding an oil which was subjected to column chromatography (NH3 sat'd 3% MeOH/CHCl3) to yield 0.14 g (0.62 mmol, 356?) of the desired product.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:29])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[NH:24][CH:25]3[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[N:16]=1)=[O:4].CO.[Li+].[OH-].CC(O)=O>C1COCC1>[CH:25]1([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15]3[N:16]=[C:12]([NH:11][C:10]([C@@H:6]4[CH2:7][CH2:8][CH2:9][C@H:5]4[C:3]([OH:4])=[O:2])=[O:29])[S:13][CH:14]=3)=[CH:18][CH:19]=2)=[O:28])[CH2:26][CH2:27]1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCC[C@H]3C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Rac-trans-2-[4-(4-Cyclopropylcarbamoyl-phenyl)-thiazol-2-ylcarbamoyl]-cyclopentanecarboxylic acid methyl ester (100 mg) was dissolved in THF:MeOH:H20 (2:2:1, 5 mL) and treated with LiOH (10 eq. 45 mg) and stirred at room temperature for 15 hours. The mixture was neutralized with HOAc, and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 400.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([CH2:22][OH:23])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@H:12]([CH2:22][O:23][C:27](=[O:28])[NH:26][CH2:24][CH3:25])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CO
Solvent: Cc1ccccc1
Product: CCNC(=O)OC[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C

Procedure:
120.0 mg (0.3 mmol) tert. Butyl (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-hydroxymethyl-pyrrolidine-1-carboxylate are refluxed in 5 ml of toluene with 30 μl (0.38 mmol) ethylisocyanate for three hours. Then 100 μl ethyl isocyanate are added three times at three hour intervals and the mixture is refluxed for a further 16 hours. Then the mixture is cooled, evaporated to dryness and purified by flash chromatography on silica gel (eluant DCM/methanol 100:3).
Reaction SMILES: [CH:1]1([PH:7](=[S:14])[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C1(C)C=CC=CC=1>[CH:1]1([P:7]([Cl:16])([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[S:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: S=[PH](C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: S=P(Cl)(C1CCCCC1)C1CCCCC1
Reaction time: 4 h

Procedure:
A solution of 23 g (0.1 mol) dicyclohexylphosphine sulfide in 50 ml toluene was dropped into a suspension of 21 g (0.1 mol) PCl5 in 50 ml toluene. The reaction was exothermal and reached a maximum temperature of 35° C. After 4 hours, the low boilers were removed from the clear yellowish solution under vacuum. Yield: 24.3 g (91.5% of the theoretical). 31P-NMR: δ P=119.3 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](N)=[N:4][CH:3]=1.[CH3:10]CN(C(C)C)C(C)C.O=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([O:23]C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:10][C:5]2[C:6]([N:7]=1)=[N:8][C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:21]([OH:23])[N:4]=2
Reactant: Nc1ncc(Cl)nc1N
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 6-chloro-2,3-pyrazinediamine (3-1) (15.3 g, 107 mmol), DIPEA (37.2 mL, 213 mmol), and methyl oxo(phenyl)acetate (26.2 g, 160 mmol) in THF (300 mL) was stirred at room temperature for 2 days. The solvent was concentrated under reduced pressure, and EtOAc was added. The resulting solid was collected by filtration to give 6-chloro-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-2) as yellow powder.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[C:59](B(O)O)[CH:58]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:30])[C:2]=2[C:59]2[CH:58]=[N:57][C:66]3[C:61]([CH:60]=2)=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Yield: 95 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-quinolinylboronic acid instead of 3-pyridinylboronic acid and being purified by silica gel column chromatography (acetone/hexanes=1:3) to obtain the title compound (95%).
Reaction SMILES: [CH:1]([CH:4]1[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)=[CH:2][CH3:3].[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14]>>[C:12]([O:16][CH:2]([CH3:3])[CH2:1][CH:4]1[O:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9]1)(=[O:15])[CH:13]=[CH2:14]
Reactant: CC=CC1OCC(C)(C)CO1
Reactant: C=CC(=O)O
Product: C=CC(=O)OC(C)CC1OCC(C)(C)CO1

Procedure:
2-Propenyl-5,5-dimethyl-1,3-dioxane (PDD) was reacted with acrylic acid under the same conditions as the reaction with EDD (see Monomer IF).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][O:4][CH3:5].C1C(=O)N([Br:30])C(=O)C1>ClCCl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])[N:15]=2
Reactant: COCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COCC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a stirred solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.2 g, 23.4 mmol) in dichloromethane (100 ml) was added NBS (4.6 g, 25.8 mmol). After 4 h, the solvent was removed. The product was purified on a silica column using petroleum ether: ethyl acetate 2:1 as eluent. This gave the product (7.3 g, 81.1%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:14]([NH:13][C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 39.1 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5 -(tert-butylamino)-cyclohexanecarboxylate (56 mg, 0.18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg, 0.22 mol), EDCI (42 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), and Et3N (22 mg 0.20 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%-5%-10% (NH4OH/MeOH)/CH2Cl2) to give 34 mg of the title product, (1R,2S,5R)-methyl 5-(tert-butylamino)-2-((S)-2-oxo-3-(3-(trifluoromethyl)-benzamido)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=484.24.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][S:18]([OH:21])(=O)=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:24][S:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:21])=[O:19]
Reactant: O=C(OCc1ccccc1)N1CCCC(CS(=O)(=O)O)C1
Reactant: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCCC(CS(=O)(=O)Cl)C1

Procedure:
The title compound was prepared by the method of Preparation 58 from 1-[(benzyloxy)carbonyl]-3-piperidylmethanesulfonic acid [see Preparation 61]and thionyl chloride to afford benzyl 3-[(chlorosulfonyl)methyl]-1-piperidinecarboxylate as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:14]>CC(N(C)C)=O>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:2]2[N:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:25]1)[CH3:14]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Clc1nccc(-c2cccs2)n1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nccc(-c4cccs4)n3)CC2)ccc1OC
Yield: 18.1 %

Procedure:
A solution of 2-chloro-4-thiophen-2-yl-pyrimidine (29.5 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 220° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 11.5 mg (15%) of the title compound. MS (ISP): 425.3 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1([C:11]([OH:13])=O)[CH2:8][C:7]1([Cl:10])[Cl:9]>C1C=CC=CC=1>[Cl:5][C:6]1([C:11]([Cl:3])=[O:13])[CH2:8][C:7]1([Cl:10])[Cl:9]
Reactant: O=C(O)C1(Cl)CC1(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C1(Cl)CC1(Cl)Cl
Reaction time: 20 h

Procedure:
Thionyl chloride (50 ml) was added to a solution of 1,2,2-trichlorocyclopropane carboxylic acid (47.4 grams) in 300 ml of benzene. The reaction mixture was heated to reflux temperature and stirred for approximately 20 hours. The solvents were evaporated in vacuo to provide the intermediate acid chloride derivative, 1,2,2-trichlorocyclopropane carboxylic acid chloride (43.8 grams).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.I([O-])(=O)(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=[O:17]
Reactant: O=[N+]([O-])c1ccc(N2CCCC2CO)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: O=CC1CCCN1c1ccc([N+](=O)[O-])cc1F

Procedure:
[1-(2-Fluoro-4-nitro-phenyl)-pyrrolidin-2-yl]-methanol (100 mg, 0.42 mmol) and Dess-Martin periodate (175 mg, 0.42 mmol) is stirred in CH2Cl2 overnight. After chromatography, the desired product is isolated (100 mg, ˜100%): 1H NMR (300 MHz, CDCl3) 9.67 (1H, s), 7.85-7.98 (2H, m), 6.66 (1H, t, J=9.0 Hz), 4.65-4.72 (1H, m), 3.49-3.75 (2H, m), 1.89-2.30 (4H, m).
Reaction SMILES: [Br:1]Br.[C:3]([CH:5]([C:9](=[O:11])[CH3:10])[C:6]([NH2:8])=[S:7])#[N:4].C(=O)(O)[O-].[Na+].C(OC)(C)(C)C>C(O)(=O)C>[NH2:8][C:6]1[S:7][N:4]=[C:3]([Br:1])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: BrBr
Reactant: CC(=O)C(C#N)C(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(=O)c1c(Br)nsc1N

Procedure:
Add bromine (195; mL, 3.81; mol) over 10; min to a heated solution of 2-cyano-3-oxo-thiobutyramide (550; g, 3.86; mol) in glacial acetic acid (5.80; L) at 40° C. and stir at room temperature for 15; h. Filter the reaction mixture, wash the collected solid with water and dry overnight under vacuum to give a dark red solid (1151; g). Slurry the solid with stirring in a saturated aqueous solution of sodium bicarbonate (8; L) for 30; min and filter. Wash the collected solid with water and dry overnight under vacuum to give a dark red solid (1022; g). Slurry the solid with stirring with methyl t-butyl ether (5.90; L) over 1 hour, filter and retain the filtrate. Repeat the above methyl t-butyl ether extraction process twice on recovered solid retaining the filtrate after each extraction. Combine the filtrates and concentrate to give the title compound as a yellow solid which is carried on without further purification (598; g, 72%). MS (m/z): 221, 223; (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:11]/[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][CH3:10].Br[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[C:19]([F:26])([F:25])[C@@:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([NH:11][S@@:12]([C:14]([CH3:16])([CH3:17])[CH3:15])=[O:13])[CH2:9][CH3:10])[CH3:24]
Reactant: CC/C(=N\[S@](=O)C(C)(C)C)c1ccccc1F
Reactant: CCOC(=O)C(F)(F)Br
Product: CCOC(=O)C(F)(F)[C@](CC)(N[S@](=O)C(C)(C)C)c1ccccc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-phenyl)-prop-(E)-ylidene]-amide (intermediate A2F) and ethyl 2-bromo-2,2-difluoroacetate, the product (R)-2,2-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-pentanoic acid ethyl ester was obtained as a colorless oil. MS (ISP): m/z=380.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[C@@H:9]([OH:12])[CH2:10]Cl)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C@@H:9]1[CH2:10][O:12]1)[CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H]1CO1
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To a stirred solution of (R,R)-1-(2,5-difluorophenylmethyl)-3-chloro-2-hydroxypropylcarbamic acid tert-butyl ester (2.2 g, 6.6 mmol) in ethanol (100 mL) at 0° C. is added a 0.5M solution of KOH in ethanol (15.7 mL, 7.9 mmol, 1.2 eq) and is stirred for 90 min. The reaction mixture is concentrated under reduced pressure and the residue is redissolved in ethyl acetate. The solution is washed sequentially with saturated ammonium chloride (aq), water and brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a white solid (1.86 g, 6.2 mmol).