Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[OH:27][CH:28]1[CH2:31][NH:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:30]2[CH2:31][CH:28]([OH:27])[CH2:29]2)=[O:16])=[CH:20][CH:21]=1
Reactant: OC1CNC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC(O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (100 mg, 0.28 mmol), 3-hydroxyazetidine hydrochloride (Heterocycles, 2002, 56(1–2), 433–442; 30 mg, 0.28 mmol) and HOBt (37 mg, 0.28 mmol) were dissolved in DMF (5 ml) and DIPEA (0.14 ml, 0.83 mmol). After 5 min, EDCI (69 mg, 0.36 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the residue triturated with water. Purification by chromatography on silica gel eluting with methanol:dichloromethane (1:49 to 3:97) gave the title compound as a yellow solid. δH (CD3OD): 3.08–3.21 (2H, m), 3.58–3.63 (0.5H, m), 3.84–3.91 (0.5H, m), 4.03–4.09 (0.5H, m), 4.25–4.32 (0.5H, m), 4.38–4.94 (4H, m), 7.03–7.12 (2H, m), 7.15–7.19 (1H, m), 7.30–7.38 (2H, m), 7.68 (1H, s), 8.59 (1H, s); RT=3.32 min.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[CH3:18][C:19]([CH3:21])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:19]1([CH3:21])[CH3:18])[CH3:2]
Reactant: CC(C)=O
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred overnight at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate) to afford the title compound (0.0898 g, 63%) as a yellow solid:
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]1([NH:17][C:18]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)CCl>[CH3:27][O:26][C:24]([C:18]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:1][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:17]=1)=[O:25]
Reactant: CN(C)C=O
Reactant: COC(=O)C=C(Nc1ccccc1)C(=O)OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccccc2nc1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of dimethylformamide (DMF, 0.1 mol) in ethylenedichloride (EDC, 100 ml), cooled in an ice bath, is added dropwise with stirring phosphorous oxychloride (POCl3, 0.10 mol). The resulting solution is stirred for one and one-half hours at room temperature and then cooled in an ice bath. To the cooled solution is then added, in small increments, a solution of dimethyl 3-phenylaminobut-2-ene-dioate in ethylene dichloride. The resulting mixture is thereafter heated to reflux for three hours, cooled, and washed with half saturated brine. The organic phase is separated from the aqueous phase and dried. The solvent is removed under vacuum, and the residue recrystallized from methanol to afford 18.2 g (0.074 mol) of dimethyl-2,3-quinolinedicarboxylate, mp 105°-106.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24].ClCCl>N1C=CC=CC=1>[NH3:1].[CH2:23]([S:25]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:27])=[O:26])[CH3:24]
Reactant: CCCCCCN1CCC(CCC)(c2cccc(N)c2)CC1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CCC(CCC)(c2cccc(NS(=O)(=O)CC)c2)CC1
Product: N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.8 %

Procedure:
To a solution of 4-(3-aminophenyl)-N-hexyl-4-n-propylpiperidine (Preparation 70, 34 mg, 0.11 mmol) in pyridine (0.5 ml) under nitrogen was added ethanesulfonyl chloride (16 ml, 0.17 mmol) and the resultant mixture was stirred overnight. Ice (2 g) was added and, after 15 min, dichloromethane (3 ml) was added and the biphasic mixture was left to stir for 15 min. The layers were separated and the aqueous layer was extracted with dichloromethane (3 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by silica (5 g) column chromatography eluting with ethyl acetate:hexane:0.880 ammonia (40:60:1 to 75:25:1) to give the title compound as a pale yellow oil (26 mg, 60%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[N:18]=[C:17](C(Cl)(Cl)Cl)[N:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1.Cl.[CH3:28][OH:29]>>[NH2:12][C:13]1[N:18]=[C:17]([O:29][CH3:28])[N:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1
Reactant: CO
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(N)nc(C(F)(F)F)n1
Temperature: 20 °C

Procedure:
2.7 g (18 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene were added at 22° C. to a solution of 5 g (18 mmol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine in 25 ml of methanol. The mixture was refluxed for 1 hour and, after cooling to 20° C., made weakly acid (pH=6) with 2 normal aqueous hydrochloric acid. Then most of the solvent was removed under reduced pressure, after which the solid was isolated in a conventional manner.
Reaction SMILES: [CH2:1]([C:4]1([CH2:21][CH2:22][CH3:23])[CH2:20][CH2:19][C:7]2([CH:12](C#N)[C:11](=[O:15])NC(=O)C2C#N)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Cl.[C:25]([OH:28])(=[O:27])[CH3:26].[OH2:29]>>[CH2:1]([C:4]1([CH2:21][CH2:22][CH3:23])[CH2:20][CH2:19][C:7]([CH2:12][C:11]([OH:29])=[O:15])([CH2:26][C:25]([OH:28])=[O:27])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O
Reactant: CC(=O)O
Reactant: CCCC1(CCC)CCC2(CC1)C(C#N)C(=O)NC(=O)C2C#N
Agent: Cl
Product: CCCC1(CCC)CCC(CC(=O)O)(CC(=O)O)CC1
Temperature: 25 °C
Yield: 35 %

Procedure:
9,9-Dipropyl-1,5 -dicyano-3 -azaspiro[5.5]undecane-2,4 -dione, prepared according to the method of Example 17, was dissolved in a solution of concentrated hydrochloric acid/acetic acid/water (4/7/1) and the solution was heated at reflux for 2 3 days. The reaction mixture was cooled to room temperature and the volatile materials were removed on the rotavap. The residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the desired acid which was recrystallized from ethyl acetate/hexanes; yield 35-50%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([NH:18][C:19]1[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:10]([NH:18][C:19]1[CH:24]=[CH:23][N:22]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:21](=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
tert-Butyl bromoacetate (24 ml; 0.15 mol) is slowly added dropwise, at room temperature, to a suspension of N4 -benzoylcytosine (21.5 g; 0.1 mol) and potassium carbonate 13.8 g; 0.1 mol) in anhydrous N,N-dimethylformamide (2.15 l). The heterogeneous mixture is stirred vigorously at room temperature for 20 h and insoluble starting material is subsequently filtered off with suction; the filtrate is concentrated in vacuo and the residue is subsequently distilled repeatedly with toluene and then taken up in chloroform (1.0 l); it is then extracted once by shaking with water (0.3 l), and the phases are swiftly separated. The organic phase is filtered once more and concentrated. Yield: 15.23.g (46%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH2:10].[CH3:11][CH:12]([CH3:15])[C:13]#[CH:14]>CCN(CC)CC.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>[CH3:9][O:8][C:6]1[N:5]=[CH:4][C:3]([NH2:10])=[C:2]([C:14]#[C:13][CH:12]([CH3:15])[CH3:11])[CH:7]=1
Reactant: COc1cc(I)c(N)cn1
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C#CC(C)C)c(N)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-iodo-6-methoxypyridin-3-amine (Compound 3, 845 mg, 3.4 mmol) in Et3N (12 ml) in a re-sealable pressure tube was added Pd(PPh3)2Cl2 (24 mg, 0.034 mmol), Cul (7.0 mg, 0.034 mmol), and 3-methyl-1-butyne (0.66 ml, 6.8 mmol). The mixture was stirred at room temperature for 20 h and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as beige solid.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[O:10]1[CH2:11][CH2:12][N:7]([CH2:2][CH:3]([OH:6])[CH2:4][OH:5])[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: OCC(O)CCl
Product: OCC(O)CN1CCOCC1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
33 g of 3-chloropropylene glycol was added dropwise to 65 g morpholine, with stirring, while maintaining the temperature at 80° C. The 3-chloropropylene glycol reacted quickly with the morpholine exothermically. The reaction mixture was stirred for 3 hours, with the temperature maintained at 80° C. The salt of morpholine, which separated from the reaction mixture, was filtered out. The filtrate was distilled under reduced pressure. This distillation gave 35 g of the desired product, 3-morpholino propylene glycol (bp. 135°-138° C./11 mmHg), in a 75.5% yield.
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[Na+].[CH3:9][NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:27]([O:61][CH3:62])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:59][CH3:60])[C@@H:37]([CH3:58])[C:38]([NH:40][C@@H:41]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH:12]([CH3:14])[CH3:13].C([BH3-])#N.[Na+].Cl.C([O:76][C:77](=[O:106])[CH2:78][C@@H:79](OC)[C@@H](N(C(=O)[C@H](C(C)C)NC(OCC1C=CC=CC=1)=O)C)[C@@H](C)CC)(C)(C)C>>[C:77]([CH2:78][CH2:79][CH2:9][N:10]([CH3:2])[C@H:11]([C:15]([NH:17][C@H:18]([C:22]([N:24]([C@@H:26]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:27]([O:61][CH3:62])[CH2:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C@H:36]([O:59][CH3:60])[C@@H:37]([CH3:58])[C:38]([NH:40][C@@H:41]([CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:39])=[O:30])[CH3:25])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH:12]([CH3:14])[CH3:13])([OH:106])=[O:76]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=C([O-])C(F)(F)F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
24 mg (26 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-phenylpropane-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide sodium trifluoroacetate (intermediate 33) and 33.7 μl of 15% aqueous amber aldehyde acid solution (52 μmol) were dissolved in 953 μl of a 1:1-dioxane/water composition and heated for 1 hour at a temperature of 100° C. After a short cooling period 1.80 mg (29 μmol) of sodium cyanoborohydride were added. The reaction composition was formulated with 0.1 of N hydrochloric acid to pH 3 and heated for 2 hours at a temperature of 100° C. It was reheated again for 2 hours at 100° C. after the same amounts of amber aldehyde acid solution, sodium cyanoborohydride, and hydrochloric acid had been added once again. Afterwards, the reaction composition had been separated directly by means of preparative HPLC. The yield was 15.2 mg (65% o. th.) of the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1.CN1CCOCC1>ClCCl>[C:27]([O:26][C:24]([CH2:23][O:22][CH:19]1[CH2:18][CH2:17][N:16]([C:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[O:15])[CH2:21][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Yield: 88.7 %

Procedure:
5.8 g of Z-glycine are first activated with 5.4 g of CDMT and then coupled with 6.0 g of t-butyl 4-piperidinyloxyacetate and 6.3 ml of N-methylmorpholine in dichloromethane there are obtained 10 g of benzyl [[[4-[(t-butoxycarbonyl)methoxy]piperidinyl]carbonyl]methyl]carbamate. MS (EI): 406 (M+).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:7][N:6]([CH3:18])[CH:5]=1)(=[O:3])C.ClN1C(=O)CCC1=O.[Cl:27][CH2:28][Cl:29]>>[Cl:27][CH:28]([Cl:29])[C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:7][N:6]([CH3:18])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cn(C)cc(-c2cccc(Cl)c2)c1=O
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Cl
Product: Cn1cc(C(=O)C(Cl)Cl)c(=O)c(-c2cccc(Cl)c2)c1

Procedure:
A 1.1 g. portion of 3-acetyl-5-(3-chlorophenyl)-1-methyl-4(1H)-pyridinone was dissolved in 100 ml. of dichloromethane, and to it was added dropwise a solution of 1.06 g. of N-chlorosuccinimide in 50 ml. of dichloromethane. After the addition, the reaction mixture was stirred at reflux for 2 days, during which time two additional 0.5 g. portions of N-chlorosuccinimide were added. The mixture was then cooled, diluted with additional dichloromethane, and washed twice with 2 N sodium hydroxide solution. The organic portion was dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was recrystallized from dichloromethane/hexane to obtain 0.4 g. of the desired product, m.p. 201°-202°. Nmr analysis in DMSOd6 showed peaks at δ8.50-8.55 (d, 1H, pyridine); 8.10-8.16 (d, 1H, pyridine); 7.3-8.8 (m, 5H, aromatic and CHCl2); 3.81 (s, 3H, N--CH3).
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[F:9][C:10]([F:53])([F:52])[C:11]1[CH:12]=[C:13]([C@H:21]2[O:25][C:24](=[O:26])[N:23]([CH2:27][C:28]3[C:33]([C:34]4[C:35]([O:47][CH3:48])=[N:36][CH:37]=[C:38]([C:40]([OH:46])([CH3:45])[C:41]([F:44])([F:43])[F:42])[CH:39]=4)=[CH:32][N:31]=[C:30](SC)[N:29]=3)[C@H:22]2[CH3:51])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.[C:54](#N)C>O.C(OC)(C)(C)C>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C@H:21]2[O:25][C:24](=[O:26])[N:23]([CH2:27][C:28]3[C:33]([C:34]4[C:35]([O:47][CH3:48])=[N:36][CH:37]=[C:38]([C:40]([OH:46])([CH3:45])[C:41]([F:44])([F:43])[F:42])[CH:39]=4)=[CH:32][N:31]=[C:30]([S:1]([CH3:54])(=[O:6])=[O:2])[N:29]=3)[C@H:22]2[CH3:51])[CH:12]=[C:11]([C:10]([F:53])([F:52])[F:9])[CH:16]=1
Reactant: COc1ncc(C(C)(O)C(F)(F)F)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC#N
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ncc(C(C)(O)C(F)(F)F)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Potassium peroxymonosulfate (528 mg, 0.859 mmol) was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-{2-methoxy-5-[(2RS)-1,1,1-trifluoro-2-hydroxypropan-2-yl]pyridin-3-yl}-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step A, 240 mg, 0.358 mmol) in acetonitrile (2 mL) and water (1 mL) and stirred for 1 hour at 60° C. (bath was turned off immediately and allowed to cool to 25° C. over 1 hour); LCMS showed complete conversion to product. The reaction was diluted with 20 mL methyl t-butyl ether and poured into 20 mL water; the organic layer was washed twice with water (20 mL) and finally with 50 mL brine, dried over sodium sulfate and concentrated to afford white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C([Li:14])(C)(C)C.C=CC=C.C=CC1C=CC=CC=1>C1CCCCC1.CCCCC>[Li:14][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9]
Reactant: [Li]C(C)(C)C
Reactant: CN1CCCC1CCCl
Agent: C=CC=C
Solvent: C=Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CCCCC
Product: [Li]CCC1CCCN1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-chloroethyl)-1 -methylpyrrolidine was dissolved in cyclohexane and reacted with about two molar equivalents of t-butyllithium in pentane in an inert atmosphere including argon or nitrogen. The resulting mixture was agitated gently at room temperature for about an hour. The mixture was allowed to stand overnight and used to initiate the polymerization of butadiene and styrene as described in the following examples.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C-:8]#[N:9].[Na+].[NH4+:11].[Cl-].N.CO.N>CO>[NH2:11][CH:1]([C:8]#[N:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: O=Cc1ccco1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N#CC(N)c1ccco1

Procedure:
Furfural (1.0 equiv) is mixed with NaCN (1.1 equiv) and NH4Cl (1.1 equiv) in 2 Molar NH3/MeOH (4 equiv NH3). The flask is fitted with a reflux condenser and mixture is refluxed. At the end of each of the first 3 h an additional equivalent of NH3 in MeOH is added. The reaction mixture is cooled and the excess solids are filtered away on a frit. The filtrate is concentrated by rotary evaporation and the residue is triturated with diethyl ether and the mixture is filtered again. The filtrate is concentrated on a rotovap. The product is purified, if necessary, by flash chromatography on silica gel with EtOAc/hexanes as an eluent to yield amino-cyano-(furan-2-yl)methane.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH2:10][O:11][C:12](/[CH:14]=[CH:15]/[CH2:16]P(OCC)(OCC)=O)=[O:13].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[C:32]2[CH:40]=O)[CH:26]=1>O1CCCC1>[CH2:10]([O:11][C:12]([CH:14]=[CH:15][CH:16]=[CH:40][C:32]1[N:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C:39]2[C:34]([CH:33]=1)=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:13])[CH3:9]
Reactant: O=Cc1cc2ccccc2n1-c1cccnc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1cc2ccccc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of lithium diisopropylamide (from 0.57 ml of diisopropylamine and 2.5 ml of 1.6M n-butyllithium in hexane) in 20 ml of dry tetrahydrofuran under nitrogen is cooled to -70° and 0.78 ml of triethyl 4-phosphonocrotonate is added dropwise. The reaction mixture is stirred for 30 minutes at -70°, and then a solution of 0.9 g of N-(3-pyridyl)indole-2-carboxaldehyde in 5 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm to room temperature, is stirred for 14 hours and is evaporated to an oil which is partitioned between 15 ml of half-saturated ammonium chloride solution and 40 ml of ethyl ether. The organic phase is washed with 10 ml of water, dried over sodium sulfate and evaporated to yield 2-[4-(ethoxycarbonyl)butadienyl]-N-(3-pyridyl)indole as a waxy solid; Rf (10% methanol and toluene, silica gel)=0.7.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[Li+].[OH-]>C1COCC1.CO.O>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:44])=[O:2])=[CH:12][CH:11]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(C)(C)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(C)(C)C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.4 %

Procedure:
A mixture of chiral 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-2-methyl-propionic acid methyl ester (21 mg, 0.0327 mmol) was dissolved in THF (3 mL) and methanol (1 mL), followed by 2N LiOH (1 mL). The reaction mixture was stirred at room temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate (2×). The organic phase was separated then concentrated under reduced pressure to afford crude product. The compound was purified by RP-HPLC (30%-95% of acetonitrile/water) to afford of chiral 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-2-methyl-propionic acid (12 mg, 58.4%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H33Cl2F2N3O3+H [(M+H)+]: 628.1940. found: 628.1937.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[F:13].Cl[CH2:16]Cl.C[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21].ClC(Cl)C>C(OCC)C>[F:24][C:23]([F:26])([F:25])[S:20]([O-:22])(=[O:21])=[O:19].[F:13][C:5]1[CH:6]=[C:7]([N+:10]([CH3:16])([CH3:11])[CH3:12])[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(N(C)C)cc1F
Reactant: ClCCl
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc([N+](C)(C)C)cc1F
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Yield: 80 %

Procedure:
To a stirred solution of 2.46 g (12.5 mmol) 4a and 50 ml dichloromethane were added 20.5 g (125 mmol) methyltriflate (Aldrich) drop wisely. The reaction mixture was refluxed for 2 days. The solvent was carefully substituted by dichloroethan. The reaction mixture was refluxed for 2 days and then cooled to room temperature. Diethylether was added. The desired compound precipitates and the solvent was decanted. The solid was washed extensively (ten times) with large amounts of diethylether. The solid was dried by use of oil pump vacuum and purified by (C-18) RP-column chromatography (acetonitril/water-gradient 1:99 to 80:20). The desired compound 4b was obtained in 80% yield (3.61 g, 10.0 mmol).