Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.[CH3:23][C:24](=O)[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:11][C:9]1([CH3:12])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]([CH3:25])[CH3:23])[CH2:4][C@@H:5]([N:13]3[C:17]4[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=4[CH:15]=[CH:14]3)[C@@H:6]2[O:10]1
Reactant: CC(C)=O
Reactant: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NC[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.024 g, 3.38 mmol) was dissolved in DCE (35 ml) and propan-2-one (0.50 ml, 6.75 mmol) was added and the reaction left for 15 mins. Sodium triacetoxyborohydride (1.002 g, 4.73 mmol) was added and the reaction left overnight. The reaction was quenched by the addition of sat. Na2CO3 solution (35 ml) and DCM (35 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×35 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM and 15% 2M NH3 in MeOH:85% DCM as eluent to give the product as a white foamy solid (0.941 g, 81%): MS (ESI+) for C18H27N5O2 m/z 346.1 [M+H]+, 368.1 [m+Na]+; LCMS: Compound in solvent front; 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.04 (d, J=3.63 Hz, 1H), 6.36 (d, J=3.47 Hz, 1H), 5.08 (br. s., 2H), 4.87-5.02 (m, 2H), 4.54 (t, J=6.38 Hz, 1H), 2.80-2.90 (m, 2H), 2.70-2.80 (m, 1H), 2.46 (dt, J=12.77, 6.54 Hz, 1H), 2.30-2.37 (m, 1H), 2.17 (q, J=11.98 Hz, 1H), 1.57 (s, 3H), 1.31 (s, 3H), 1.09 (t, J=5.44 Hz, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:18]([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([OH:25])=[O:24]>C1COCC1>[CH2:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]1[O:20][CH2:22][C:23]([OH:25])=[O:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CBr
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a suspension of sodium hydride (1.1 g, 38.5 mmol) in THF (30 mL) at room temperature was added a solution of compound 20 (2.0 g, 8.37 mmol) in THF (15 mL) and the resulting reaction mixture was allowed to stir at room temperature for 1 hour. Thereafter a solution of bromo acetic acid (2.68 g, 19.25 mmol) in THF (5 mL) was added dropwise and the resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture is poured onto water and extracted with ethyl ether (3×100 mL) and the combined ethyl ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography (SiO2, 20 to 70% EtOAc-Hexanes eluant) provided 1.0 g of 22 as a clear oil (2.48 g, theoretical, 40% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)[CH3:3].[CH2:12]1[NH:14][CH2:13]1.CS(O)(=O)=O>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][O:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:1]
Reactant: C1CN1
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(COCCN)o1
Reaction time: 18 h
Yield: 2.5 %

Procedure:
To a solution of 5-(dimethylamino)methyl-2-furanmethanol (6.2 g) and ethylene imine (2.82 g) in dry tetrahydrofuran was added a solution of methanesulphonic acid (11.6 g) in tetrahydrofuran (40 ml). The solution was evaporated and the oily residue heated at 98°-100° for 10 mins. After 18 hr, 5N sodium hydroxide (60 ml) was added and the solution evaporated to dryness. Anhydrous sodium sulphate and ethyl acetate (150 ml) were added and after 2 hr the suspension was filtered, treated with decolourising charcoal and evaporated. The resulting oil was chromatographed on silica, firstly with methanol-ammonia 0.88 79:1, and the eluate discarded, and secondly with methanol-ammonia 0.88 19:1. This eluate was evaporated to give an oil from which the bisoxalate salt of 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine (from ethanol) 0.2 g, m.p. 125°-128°, was obtained. Route (ii)
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.C(N(CC)CC)C.[CH2:23]([SH:27])[CH2:24][CH2:25][CH3:26].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[CH2:23]([S:27][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCS
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCSc1c2sc3ccccc3nc-2ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of phenothiazin-3-one (0.21 g) in 20 ml THF was added triethylamine (0.28 ml) and n-butanethiol (0.2 ml). The mixture was refluxed for 15 hours and then cooled to room temperature. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.22 g) was added and the reaction was stirred for 2 hours at 25°. The solvent was removed in vacuo. The residue was chromatographed on neutral alumina (Act III) and eluted with 15% EtOAc/hexane to afford the title compound, m.p. 72° C.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH2:3]1.C1CCN2C(=NCCC2)CC1.[B-](F)(F)(F)F.CCN([S+](F)F)CC>C(Cl)Cl>[O:19]=[C:5]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:2]=[CH:3][N:4]1[C:20]1[CH2:21][O:22][C:23](=[O:25])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(C1=CC(=O)OC1)CC2O
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C=CN(C3=CC(=O)OC3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxy-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (210 mg, 0.596 mmol) in DCM (6 mL) at 0° C. was added DBU (269 μl, 1.79 mmol), and XtalFluor-E® (409 mg, 1.79 mmol). The reaction mixture was stirred overnight while warming up to rt, then quenched with aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1)]+=335;
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To 0.80 g (2.8 mmol) of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 0.43 g (2.8 mmol) of 1,8-diazobicyclo [5.4.0]undec-7-ene, was added 0.35 g (3.1 mmol) of N-methyl-3-pyrrolidinemethanamine. The mixture was refluxed for one hour and stirred overnight. The solids were filtered and washed with acetonitrile: ether (1:6) to give 0.81 g of the title compound, mp 265°-267° C.
Reaction SMILES: [OH:1][C@@:2]([CH2:51][CH2:52][CH3:53])([C@@H:10]([C:28](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)OC1=S)=[O:29])/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:54][C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[C:70][CH3:71])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH2:68]([O:67][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][C@H:55]([NH:54][C:28]([C@@H:10](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[O:20])[C@@:2]([OH:1])([CH2:51][CH2:52][CH3:53])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:29])[C:56]([O:58][CH3:59])=[O:57])=[CH:66][CH:65]=1)[C:69]#[C:70][CH3:71]
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CCC[C@@](O)(C(=O)OC(C)(C)C)[C@H](/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)C(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 40 °C
Yield: 8.1 %

Procedure:
tert-Butyl (E)-(2S,3S)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-propyl-10-(2-trimethylsilanyl-ethoxycarbonylamino)-dec-4-enoate (582 mg, 0.759 mmol) and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (376 mg, 1.52 mmol) were dissolved in dichloromethane (10 mL), and dichloromethane was then distilled off under reduced pressure. The obtained mixture was warmed at 40° C. for 41 hours. The reaction mixture was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 443 mg (0.0618 mmol, 81% yield) of tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-propyl-10-(2-trimethylsilanyl-ethoxycarbonylamino)-dec-4-enoate.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[S:8][N:7]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[S:8]1)=[O:4]
Reactant: CN=C=O
Reactant: CCCOc1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
10 ml of methyl isocyanate were added to a solution of 16.01 g of 3-hydroxy-5-n-propoxy-1,2,4-thiadiazole, 0.5 ml of triethylamine and 200 ml of tetrahydrofuran and the mixture was stirred for 20 hours at 20° C. The mixture was evaporated to dryness and the residue was twice crystallized from a 75-25 isopropyl ether-ethyl acetate mixture to obtain 12 g of 2-(N-methylcarbamoyl)-5-n-propoxy-1,2,4-thiadiazole-3-one melting at 112° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12].[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>CN(C=O)C.CCOCC>[Cl:12][C:4]1[C:5]([F:11])=[N:6][C:7]([F:10])=[C:8]([F:9])[C:3]=1[CH2:2][O:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Fc1nc(F)c(Cl)c(CBr)c1F
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OCc1c(F)c(F)nc(F)c1Cl)c1ccccc1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of the 4-bromomethyl-3-chloro-2,5,6-trifluoro-pyridine (15.6 g, 59.9 mmol) in DMF (90 ml) cooled in an ice bath, sodium benzoate (12.9 g, 89.8 mmol) was added. After 1 hr., the mixture was stirred in a water bath for ca. 20 hr. The mixture was then diluted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:15) to afford 11.9 g (66%) of benzoic acid 3-chloro-2,5,6-trifluoro-pyridin-4-ylmethyl ester as a white solid. m.p. 60° C.; 1H NMR (200 MHz, CDCl3) δ 5.54 (2H, d, J=1.6 Hz), 7.41-7.64 (3H, m), 8.00-8.05 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Nc1cc(F)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OC(c1nc2cc(Cl)c(F)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4-Chloro-5-fluoro-benzene-1,2-diamine (5.20 g; 32.4 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (7.00 g; 48.6 mmoles) were suspended in 6N HCl (9 mL; 54 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.90 g; 81.00 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:66][C:67]1[CH:73]=[CH:72][CH:71]=[CH:70][C:68]=1[NH2:69]>CN(C=O)C>[F:66][C:67]1[CH:73]=[CH:72][CH:71]=[CH:70][C:68]=1[NH:69][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH3:31])[CH:28]([CH3:29])[CH3:30])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Reactant: Nc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
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@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol, Eq: 1.00) and HATU (50.9 mg, 134 μmol, Eq: 1.2) were combined in DMF to give a colorless solution. Diisopropylethylamine (23.4 μL, 134 μmol, Eq: 1.2) and 2-fluoroaniline (14.9 mg, 134 μmol, Eq: 1.2) were added. The reaction was stirred at rt for 1 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (39 mg), m/z=542 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13](C)C=C[C:6]=1S([O-])(=O)=O)(=[O:3])[CH3:2].C(O)(=[O:18])C>>[OH:18][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:14]=[CH2:13]
Reactant: CC(=O)Oc1cc(C)ccc1S(=O)(=O)[O-]
Reactant: CC(=O)O
Product: C=CC(CO)OC(C)=O

Procedure:
Alternatively, the acetoxy-tosylate could be prepared by initial reaction of EpB with acetic acid under palladium(0) catalysis to afford 1-hydroxy-2-acetoxy-3-butene. Tosylation under normal conditions (p-TsCl, Et3N, CH2C12, 88%) afforded the desired product. However, the isomeric inconsistency of the monoacetate material (acetyl migration during distillative purification) and the inseparability of the positional isomers of two intermediates posed significant problems, since the unwanted isomers complicated the enzymatic hydrolysis. Therefore, the former (diol) preparation is preferred.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O>[C:16]1([CH2:15][N:12]2[CH:13]=[CH:14][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[N:11]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(Nc2ccn(Cc3ccccc3)n2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Nc2ccn(Cc3ccccc3)n2)cc1

Procedure:
The title pyrazole of Example 3 (6.3 g) was heated on a steam bath in a mixture of aqueous HBr (48%, 200 ml) and glacial acetic acid (25 ml) for 6 hours. The reaction mixture was cooled, poured into water, neutralised with sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried and evaporated to give after chromatography the title compound, 1.0 g, mp 114°-116° (from cyclohexane/ethyl acetate).
Reaction SMILES: [Br-:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])=[C:7]2[C:11]=1[O:10][CH:9]=[CH:8]2>ClC(Cl)(Cl)Cl>[Br:1][C:9]1[O:10][C:11]2[C:7](=[C:6]([CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])[CH:5]=[CH:4][C:3]=2[Cl:2])[CH:8]=1
Reactant: [Br-]
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)c2occc12
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C(C(=O)O)c1ccc(Cl)c2oc(Br)cc12
Yield: 78.9 %

Procedure:
A solution of bromide (0.90 g, 5.7×10-3 mol) and 7-chloro-α-isopropylbenzofuran-4-acetic acid (1.44 g, 5.7×10-3 mol) in tetrachloromethane (50 cm3) was heated to reflux for 2 hr. The solvent was removed and the residue was subjected to column chromatography on silica using ethyl acetate as the eluant. The appropriate fractions were combined and the solvent was removed to give 2-bromo-7-chloro-α-isopropylbenzofuran-4-acetic acid (1.50 g, 4.5×10-3 mol, 79.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1OCC1CO1)c1cccc2[nH]ccc12

Procedure:
Under an inert atmosphere, a solution of 3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 1.65 g of potassium carbonate in 100 ml of acetone was refluxed for 24 hours with 4.7 ml of epichlorhydrin and after purifying by chromatography over silica (eluent: ethyl acetate-triethylamine, 9-1) and evaporating to dryness, the residue was triturated in pentane, then filtered and dried under reduced pressure at 60° C. to obtain 2.8 g of N-[2-[(2-oxiranyl)methoxy]phenyl]-1H-indol-4-carboxamide melting at 122° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.CN(C=O)C.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([Cl:24])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Cl)cnn1-c1ccccc1
Temperature: 36 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid from Step B (11B-2) (20.2 g, 0.1 mol) in DCM (200 mL) and DMF (730 mg, 0.01 mol) was added sulfuryl dichloride (8.73 mL, 0.12 mol) at RT. The mixture was stirred at 36° C. for 2 h. The solution was concentrated under reduced pressure and DCM (200 mL) was added to the white solid residue to form a suspension of the above corresponding acyl chloride. Yield: 98%, 1HNMR CDCl3): 8.16 (s, 1H), 7.45-7.59 (m, 5H), 2.53 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][NH:16][C@@H:15]([C:19](=[O:31])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][CH:23]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:39]=[C:38]([O:40][C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:35]=1[S:45](Cl)(=[O:47])=[O:46]>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:45]([C:35]3[CH:36]=[CH:37][C:38]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:39][C:34]=3[F:33])(=[O:47])=[O:46])[C@@H:15]([C:19](=[O:31])[NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][CH:27]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1F
Solvent: c1ccncc1
Product: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2S(=O)(=O)c2ccc(OC(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a solution of the compound (50 mg) obtained in Step 6 in pyridine (0.5 ml) was added, with stirring at room temperature, 2-fluoro-4-trifluoromethoxybenzenesulfonyl chloride (46 mg). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (59 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C@H:18]1[C@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C@:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[C@H:20]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:19]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+]>C(O)C.O>[Cl:29][C:25]1[C:24]([F:30])=[C:23]([C@@H:22]2[C@:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[C@H:20]([CH2:41][C:42]([CH3:44])([CH3:45])[CH3:43])[NH:19][C@H:18]2[C:16]([NH:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[O:17])[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3[nH]c(C(=O)O)cc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A chiral 5-{[(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}-1H-indole-2-carboxylic acid ethyl ester (33 mg, 0.051 mmol) was dissolved in ethanol (15 mL), then 2N KOH (5 mL) was added and stirred 2 hours @ 50° C., then the temperature was warmed to 65° C. for 2 h, after cooling to 25° C., the reaction was diluted with water and extracted with ethyl acetate (3×). The organic phase was separated then concentrated under reduce pressure to chiral 5-{[(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}-1H-indole-2-carboxylic acid (24 mg, 76%) as a white powder. HRMS (ES+) m/z Calcd for C32H28Cl2F2N4O3+H [(M+H)+]: 625.1580 found: 625.1580.