Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29](=O)[CH2:30][CH2:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:29]([N:26]1[CH2:27][CH2:28][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
A suspension of 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (52.8 mg, 0.134 mmol) in 1,2-dichloroethane was treated sequentially with butyraldehyde (0.1 mL, 1 mmol) and acetic acid (0.1 mL, 2 mmol), stirred at ambient temperatures, under nitrogen, for 20 minutes, treated with additional acetic acid (0.2 mL, 3 mmol) and 1,2-dichloroethane, stirred at ambient temperature for 1 hour, 40 minutes, treated with sodium triacetoxyborohydride (96.7 mg, 0.457 mmol), stirred for 3 hours at ambient temperatures, diluted with chloroform and poured into excess 2.5 N sodium hydroxide. The phases were separated; the organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.25% ammonium hydroxide/2.5% methanol in chloroform to afford 5-(1-butyl-pyrrolidin-3-yloxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a light yellow foam, 30.0 mg (49.8% yield). The foam was dissolved in chloroform and methanol, treated with ethereal HCl and concentrated in vacuo at 83° C. for 13 hours to give the title product as a pale yellow foam, 26.9 mg, Mass spectrum (+EI, [M+H]+) m/z 450. 1HNMR (500 MHz, DMSO-d6): δ14.19 (s, 1H), 10.25-10.65 (m*, 1H), 8.75 (d, 1H, J=8.54 Hz), 8.56 (d, 1H, J=6.83 Hz), 8.28 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.27 (s, 1H), 7.12 (dd, 1H, J=9.15 Hz and 2.32 Hz), 5.19-5.24 (m, 1H), 3.39-3.96 (m*, 3H), 3.08-3.24 (m*, 3H), 2.00-2.63 (m*, 2H), 1.56-1.64 (m, 2H), 1.21-1.34 (m, 2H), 0.80-0.90 ppm (m, 3H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [ClH:1].[CH:2]1([C@@H:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[NH:8]S(C(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:21]O>>[ClH:1].[CH:2]1([C@H:7]([NH2:8])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1.[CH3:21][CH:6]([CH3:5])[CH2:2][C@@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[NH2:8]
Reactant: CO
Reactant: CC(C)(C)S(=O)N[C@H](c1ccccn1)C1CCCC1
Agent: Cl
Product: CC(C)C[C@H](N)c1ccccn1
Product: N[C@H](c1ccccn1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was synthesized according to General Method I utilizing HCl (2.0 M in Et2O, 31.4 mL, 62.8 mmol) and a solution of (RS)—N-((S)-cyclopentyl(pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (8.8 g, 31.4 mmol) in MeOH (100 mL). After the addition was complete the cooling bath was removed and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in Et2O (125 mL). The precipitation was filtered off and washed with Et2O (2×125 mL) and dried under reduced pressure yielding the crude product (7.7 g, 95.0% ee (S)) as a white solid. The crude product was recrystallised from t-BuOMe (150 mL), EtOH (200 mL) and MeOH (170 mL) at 80° C. The crystals formed after the solution cooled down were collected by filtration (3.3 g, 99.0% ee (S)) and the filtrate was concentrated under reduced pressure and was recrystallised again from t-BuOMe (100 mL) and MeOH (150 mL). The second crop of crystals were collected by filtration (1.3 g, 98.0% ee (S)) resulting in a combined yield of 4.6 g, 69% isolated yield). 1H NMR (400 MHz, D2O+NaOH) δ ppm 8.81 (d, J=5.5 Hz, 1H), 8.55 (t, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.99 (t, J=6.5 Hz, 1H), 4.53 (d, J=10.5 Hz, 1H), 2.63-2.50 (m, 1H), 2.11-2.01 (m, 1H), 1.84-1.40 (m, 6H), 1.24-1.12 (m, 1H). The ee of the compound was determined by acetylating small samples with AcCl (see example below for the synthesis) and analysing the products, (S)— and (R)—N-(Cyclopentyl(pyridin-2-yl)methyl)acetamides, by chiral HPLC: Daicel Chiralpak AD-H, 80:20 v/v heptane-EtOH (+0.2% Et3N), 1.0 mL/min, λ=230 nm, Rt=9.5 min (R), Rt=25.4 min (S).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17]Br)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C([Mg]Br)C.[Mg].BrCC.[CH3:27][CH:28]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:29][Mg]Cl>C1COCC1>[CH3:14][C:6]1[C:7]([OH:13])=[C:8]([CH3:12])[C:9]2[CH2:10][CH2:11][C@:2]([CH2:16][CH2:17][CH2:41][C@@H:39]([CH2:38][CH2:37][CH2:36][C@@H:35]([CH2:34][CH2:33][CH2:32][CH:28]([CH3:29])[CH3:27])[CH3:42])[CH3:40])([CH3:1])[O:3][C:4]=2[C:5]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Reactant: CC(C)CCCC(C)CCCC(C)C[Mg]Cl
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 86 %

Procedure:
3.13 g (10 millimoles) of (2RS)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were dissolved in 10 ml of absolute THF. A solution of ethyl-magnesium bromide which had been prepared by reacting 0.25 g (10.3 millimoles) of magnesium in 3 ml of THF with a solution of 1.1 g (10.0 millimoles) of bromoethane in 5 ml of THF and stirring for 1 hour at +40° C. was added dropwise to the above solution at -20° C. The resulting reaction mixture was stirred for 1 hour at -20° C. and then there were added to it the (2RS,6RS)-2,6,10-trimethyl-1-undecyl-magnesium chloride solution prepared in Example 2a, followed by 0.7 ml of an 0.5-molar solution of di-lithium tetrachlorocuprate in absolute THF. The batch was then stirred for 3 hours at -20° C. and 16 hours at room temperature. The reaction mixture was worked up as described in Example 1c and 3.7 g of α-tocopherol were isolated by bulb tube distillation at 220° C./0.2 mbar. This corresponds to a yield of 86% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=C)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].I([O-])(=O)(=O)=[O:18].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:18])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-chloro-6-vinylisonicotinate (9.6 g, 40.1 mmol) in THF (100 mL) and water (100 mL) were added osmium tetroxide (4% in water; 6.3 mL, 0.80 mmol) and sodium periodate (25.7 g, 120.0 mmol). The mixture was stirred at ambient temperature. After 30 min, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:7][CH:3]([C:2]#[CH:1])[CH2:4][CH2:5][CH3:6])[CH3:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CC(O)CCC
Agent: [Rh]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#CC(CCC)OCC(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
To a solution of 1-hexyn-3-ol (981 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.0 mL, 9.0 mmol). The reaction mixture is stirred at rt for 6 h. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel: elution with EtOAc:heptane (25:75) gives 900 mg of the product 446. 1H NMR (CDCl3) δ 4.35-4.10 (m, 5 H), 2.43 (s, 1 H), 1.90-1.65 (m, 2 H), 1.65-1.40 (m, 2 H), 1.40-1.20 (m, 3 H), 0.95 (t, 3 H)
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9]([CH2:10][OH:11])=[CH:8][C:7]2[CH:12]=[CH:13][S:14][C:6]=2[S:5]1(=[O:16])=[O:15])[CH3:3].C([Li])CCC.[S:22](=[O:24])=[O:23].[NH2:25]OS(O)(=O)=O.CC([O-])=O.[Na+]>C1COCC1.O>[OH:11][CH2:10][C:9]1[N:4]([CH:2]([CH3:1])[CH3:3])[S:5](=[O:16])(=[O:15])[C:6]2[S:14][C:13]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:12][C:7]=2[CH:8]=1
Reactant: O=S=O
Reactant: CC(C)N1C(CO)=Cc2ccsc2S1(=O)=O
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1C(CO)=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of the product from Step D (3.25 g, 12.5 mmol) in anhydrous THF (60 mL) under nitrogen at -70° C. was added n-butyllithium (2.5M, 12.5 mL, 31.4 mmol) over 5 min. The suspension was stirred for 1 h before a stream of sulfur dioxide was passed over the surface of the reaction mixture for 5 min. The mixture was warmed to ambient temperature and evaporated to give a residue which was combined with water (100 mL); this mixture was cooled (ice bath) and hydroxylamine-O-sulfonic acid (4.24 g, 37.5 mmol) and NaOAc (8.5 g, 62.5 mmol) were added. The reaction mixture was stirred at ambient temperature for 18 h and extracted with ethyl acetate (2×200 mL). The combined extracts were dried (MgSO4), filtered, and evaporated to a residue which was purified by column chromatography (silica, 50% ethyl acetate/hexane) to give a viscous oil (4.20 g, 98%).
Reaction SMILES: CC(O)C.[ClH:5].[C:6]([C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[O:20][N:19]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].[BH4-].[Na+]>CO>[ClH:5].[F:27][C:25]1[CH:24]=[CH:23][C:22]2[C:18]([CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][C:9]([CH:6]([OH:8])[CH3:7])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:14][CH2:13]3)=[N:19][O:20][C:21]=2[CH:26]=1
Reactant: CC(=O)C1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CC(O)C1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To a mixture of 50 ml of 2-propanol and 10 ml of methanol, was added 2.8 g of 4-acetyl-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)-propyl]-4-phenylpiperidine hydrochloride and 0.76 g of sodium borohydride. After stirring at ambient temperature for twenty hrs, the mixture was evaporated. The residue was stirred with 100 ml of water for ten mins and then extracted with ether. The ether extract was washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the ether solution was acidified to pH 1 with ethereal hydrogen chloride. The resultant precipitate was collected and dried to give 2.3 g (78%) of product, mp 80° C. Recrystallization from ethyl acetate/methanol (9:1) gave the analytical sample, mp 143°-147° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:37][C:38]1[C:43]([NH2:44])=[CH:42][CH:41]=[CH:40][N:39]=1>C(Cl)Cl>[NH2:44][C:43]1[C:38]([NH:37][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[N:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Reactant: Nc1cccnc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cccnc1NC(=O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[(phenylmethoxy)carbonylamino]butanoic acid (1.1 eq) was dissolved in methylene chloride (0.2M) followed by the addition of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCA) (1.2 eq) and triethylamine (1.5 eq). The mixture was stirred at room temperature under nitrogen for 30 mins, followed by addition of 2,3-diaminopyridine. The mixture was then stirred at room temperature for 48 hrs., quenched with saturated sodium carbonate and extracted with ether. The organic phase was concentrated in vacuo and chromatographed on silica gel. (10% MeOH/CH2Cl2). EI-MS m/z 329 (M+H)+.
Reaction SMILES: [ClH:1].[N:2]1([C:7](N)=[NH:8])C=CC=N1.Cl.Cl.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][C:20]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=3)=[C:15]2[CH:14]=[N:13]1.C(N(C(C)C)CC)(C)C.Cl>CO.CN(C)C=O>[OH2:31].[ClH:1].[ClH:1].[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][C:20]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:7]([NH2:8])=[NH:2])=[CH:25][CH:24]=3)=[C:15]2[CH:14]=[N:13]1
Reactant: N=C(N)n1cccn1
Reactant: NCc1ccc(C(=O)Nc2ccnc3[nH]ncc23)cc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCc1ccc(C(=O)Nc2ccnc3[nH]ncc23)cc1
Product: O
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
Pyrazole-1-carboxamidine hydrochloride (284 mg) was added to a mixed solution of N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-aminomethylbenzamide dihydrochloride (330 mg) and diisopropylethylamine (500 mg) in methanol (5 ml)-dimethylformamide (5 ml), and the mixture was stirred in a stream of nitrogen at room temperature for 8 hours. After the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=3:1) to give white crystals. The crystals were converted to hydrochloride thereof with 15% hydrochloric acid-methanol, and the hydrochloride was recrystallized from methanol-ether to give 205 mg of N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-guanidinomethylbenzamide dihydrochloride monohydrate having a melting point of 250-254° C. (dec.)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10](/[CH:12]=[CH:13]/[C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O)=[O:11])[CH3:8].CCN(CC)CC.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>C(Cl)Cl.CN(C=O)C>[F:34][C:35]([F:39])([F:38])[CH2:36][NH:37][C:16]([C:15]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:14]=1/[CH:13]=[CH:12]/[C:10]([O:9][CH2:7][CH3:8])=[O:11])=[O:18]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
315 g of oxalyl chloride (2.48 mol) were added at a temperature between 15 and 18° C. over 24 min to a mixture of 650 g of 2-((E)-2-ethoxycarbonylvinyl)-4-trifluoromethylbenzoic acid (2.25 mol), 33 ml of DMF and 7.8 l of CH2Cl2. During the addition, gas evolution was observed. The mixture was stirred at RT for 1 h and then cooled to 5° C., and 285 g of Et3N (2.81 mol) was then added at a temperature between 5° C. and 10° C. over a period of 27 min. The mixture was stirred at 5° C. for a further 10 min, then 279 g of 2,2,2-trifluoroethylamine (2.81 mol) were added at a temperature between 9° C. and 20° C. over a period of 27 min. The mixture was stirred at RT for 10 min, in the course of which a thick precipitate precipitated out, and, to improve the stirrability of the mixture, an additional 1 l of CH2Cl2 was added. The reaction was monitored by HPLC (method C; 2-((E)-2-ethoxycarbonylvinyl)-4-trifluoromethylbenzoic acid rt=5.9 min; ethyl (E)-3-[2-(2,2,2-trifluoroethylcarbamoyl)-5-trifluoromethylphenyl]acrylate rt=13.2 min). After stirring at RT for a further 50 min, the reaction was complete. Volatile constituents of the reaction mixture were then removed under reduced pressure, and the residue was taken up with 12 l of EA and washed 3 times with 2.5 l each time of water, then twice with 2.5 l each time of a saturated aqueous NaHCO3 solution and finally with 1.5 l of a saturated aqueous NaCl solution. Drying was effected over MgSO4, and the solvent was removed under reduced pressure to obtain 802 g of ethyl (E)-3-[2-(2,2,2-trifluoroethylcarbamoyl)-5-trifluoromethylphenyl]acrylate as a brown solid. This crude substance was combined with the crude product of another batch (177 g) and dissolved at 60-70° C. in 3 l of EA, and 14 l of HEP were added at this temperature in 1 l portions. The mixture was then heated to 80° C. and stirred at this temperature for 1.5 h. This mixture was then added to 5.6 l of HEP at 70° C. and the mixture was then cooled to RT with stirring over a period of 5 h. The product was then filtered off, washed with 3 l of HEP and dried under air to obtain 689 g of ethyl (E)-3-[2-(2,2,2-trifluoroethylcarbamoyl)-5-trifluoromethylphenyl]acrylate (67%) as a light brown solid. Mp: 161.5-162° C.
Reaction SMILES: C([O:3][C:4]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:26]([O-:28])=[O:27])=[C:9]([N:19]3[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[CH:20]3)[CH:10]=2)[N:5]=1)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(C)C)(C)C>ClCCl>[N+:26]([C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:4](=[O:3])[NH:5]2)=[CH:10][C:9]=1[N:19]1[CH:23]=[C:22]([CH2:24][O:25][C:36](=[O:37])[NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:21]=[CH:20]1)([O-:28])=[O:27]
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: O=C(Nc1ccccc1)OCc1cn(-c2cc3cc(C(=O)O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of the compound of Example 1 (50.0 mg, 129 μmol) in dichloromethane (2 ml) was added phenyl isocyanate (46.2 mg, 388 μmol), and the mixture was stirred overnight at room temperature. Diisopropyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration and air-dried. These were dissolved into acetic acid (5 ml) and concentrated hydrochloric acid (1 ml) was added, which was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was washed with water and ethyl acetate in sequence and then air-dried, thereby obtaining 41.0 mg of title compound as yellow powder. Yield 71%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
To a solution of (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (see example xx) (1.03 g, 1.0 eq) in dry dichloromethane (25 mL) were added freshly powdered molecular sieves (2.88 g). Phenyl boronic acid (0.74 g, 2.0 eq) was added, followed by triethylamine (0.62 g, 2.0 eq) and copper(II)acetate (0.61 g, 1.1 eq). Oxygen gas was bubbled through the reaction mixture for 5 min. The flask was sealed with a rubber septum and left under an atmosphere of oxygen by means of a balloon. After stirring at room temperature for 24 h, the mixture was filtered and the filtrate was treated with water and filtered again. The phases were separated and the organic phase dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography on silica gel with an heptane/ethyl acetate gradient yielded the title compound as a light yellow solid (0.23 g, 18%). MS (ESI): m/z=414.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]2[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/2=[N:15]\[C:16](=[O:26])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])[CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1.CCOC(C)=O>[C:11]([C:9]1[S:8]/[C:7](=[N:15]\[C:16](=[O:26])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])/[N:6]([CH2:5][CH:3]2[CH2:4][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:2]2)[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The TFA salt of Example 63C (0.25 g, 0.64 mmol) was dissolved in 3 mL of THF. The mixture was cooled to 0° C. and triethylamine (0.27 mL, 1.9 mmol) was added. Methanesulfonyl chloride (0.1 ml, 1.3 mMol) was added dropwise and the reaction was stirred at 0° C. for 30 minutes. The reaction was diluted with EtOAc, washed with water, brine, dried with MgSO4 and the solvent removed. Final product was purified by flash chromatography using a gradient from 0 to 100% EtOAc in hexane over 300 mL. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.35 (s, 9H) 2.85 (s, 3H) 3.16-3.30 (m, 1H) 3.84 (dd, J=8.14, 5.76 Hz, 2H) 3.90 (s, 3H) 4.04 (t, J=8.31 Hz, 2H) 4.42 (d, J=7.46 Hz, 2H) 6.63 (s, 1H) 6.92 (d, J=9.16 Hz, 1H) 7.34 (dd, J=8.82, 2.71 Hz, 1H) 7.91 (d, J=2.71 Hz, 1H). MS (DCI/NH3) m/z 472.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]>CCO.Cl>[N:1]1([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of morpholine (80 g, 0.91 mol) and triethylamine (232 g, 2.29 mol) in EtOH (1750 ml) was added dropwise at 0° C. a solution of methyl 3-(bromomethyl)benzoate (252 g, 1.1034 mol) in absolute alcohol (250 ml). The mixture was stirred overnight at RT. Then the mixture was concentrated and the residue obtained was taken up in 1.5N HCl (3 L) then washed with diethyl ether (3 times) and ethyl acetate. The solution was neutralized with a 10% aqueous NaOH solution and basified up to pH=8 with a 10% aqueous NaHCO3 solution. The product was extracted with CHCl3, washed with water and brine then dried over Na2SO4. The solvent was removed and the crude was purified by column chromatography CHCl3/MeOH to give methyl 3-(morpholin-4-ylmethyl)benzoate (150 g, 70%) as brown liquid.