Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](C(=O)O)([C@H]2CCOC2)C1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)O)([C@H]2CCOC2)C1
Reaction time: 18 h
Yield: 0.1 %

Procedure:
(1R,4S)-4-[(tert-Butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopent-2-ene-1-carboxylic acid (0.79 g, 2.6 mol) was dissolved in ethanol (20.0 mL), degassed-purged with N2, followed by the addition of platinum dioxide (0.150 g, 0.528 mol). The reaction mixture was placed on a Parr apparatus and hydrogenated at 55 psi H2 for 18 h. The mixture was filtered through celite pad, washed with MeOH, concentrated to provide the desired product (730 mg, 91.8%). MS calculated for C15H26NO5 (M+H) 300.2; found 200.2 (M+H-Boc).
Reaction SMILES: [CH3:1][S:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)(=[N:4][N+:5]([O-:7])=[O:6])=[O:3].[OH-].[Na+]>C1COCC1.Cl>[NH2:14][C:10]1[CH:9]=[C:8]([S:2]([CH3:1])(=[N:4][N+:5]([O-:7])=[O:6])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=N[N+](=O)[O-])c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=N[N+](=O)[O-])c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 100 mg (0.41 mmol) of (RS)—S-methyl-N-nitro-S-(3-nitrophenyl)sulfoximide in 8 ml of THF is mixed at room temperature with 3.1 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 1 hour, another 1.0 ml of the approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid is added, and it is stirred for another 45 minutes at room temperature. The batch is made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 40 mg (0.19 mmol, corresponding to 45% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:18][CH2:17]2)=[CH:11][CH:10]=1.[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C@@H:28]2[O:29][C@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[C@@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@H:27]2[O:31][C:32](=[O:33])[CH3:34])[C:3]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[CH2:18][CH2:17]2)=[CH:13][CH:14]=1
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(C=C2CC2)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(C=C3CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a suspension of 5-methyl-4-{[4-(cyclopropylidenemethyl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (0.026 g) and acetobromo-α-D-glucose (0.049 g) in tetrahydrofuran was added silver carbonate (0.036 g), and the mixture was stirred at 60° C. overnight under light shielding. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) and successively by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give 5-methyl-4-{[4-(cyclopropylidenemethyl)phenyl]methyl}-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.010 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[N:15](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:16]=[CH:17][N:18]=3)[OH:13])[C:6]3[CH2:38][CH2:39][N:40]4[CH:44]([C:5]=3[C:4]=2[CH:3]=1)[CH2:43][CH2:42][CH2:41]4>CO.Cl>[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH:12]([OH:13])[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH:44]3[N:40]([CH2:39][CH2:38][C:6]1=2)[CH2:41][CH2:42][CH2:43]3
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN2CCCC12
Agent: Cl
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ncc[nH]2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.9 %

Procedure:
A suspension of 2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(1-trityl-1H-imidazol-2-yl)ethanol (0.4 g, 0.69 mmol) in MeOH (10 mL), 1N HCl (1 mL) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture concentrated under vacuum to obtain the crude product that was basified with satd. sodium bicarbonate solution and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product, which was purified by reverse HPLC to obtain 11.30 mg 1-(1H-imidazol-2-yl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethanol. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.44 (s, 2H), 7.27 (s, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 5.37 (t, 1H), 5.1 (m, 1H), 4.56 (dd, 1H), 4.46 (dd, 1H), 3.67 (m, 3H), 3.42 (m, 1H), 3.24 (m, 2H), 2.7 (m, 1H), 2.4 (s, 3H), 2.2 (m, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C-:13]#[N:14].[Na+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:12]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:13]#[N:14])[CH:3]=2)[NH:8]1
Reactant: O=C1CCc2cc(I)ccc2N1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: N#Cc1ccc2c(c1)CCC(=O)N2

Procedure:
6-Iodo-3,4-dihydroquinolin-2(1H)-one (1.50 g; 5.50 mmol), sodium cyanide (0.54 g; 11.0 mmol), copper (I) iodide (0.105 g; 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g; 0.3 mmol) were combined in a flask equipped with a reflux condenser. The flask was subjected to several evacuation-nitrogen purge cycles followed by the addition of acetonitrile (25 mL). The reaction was heated to reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate (200 mL), filtered through CELITE diatomaceous earth and rinsed with copious amounts of ethyl acetate. The organic solution was washed twice with brine (50 mL), dried over sodium sulfate, filtered through a fritted funnel, and the volatiles were removed under vacuum. The crude residue was crystallized from methanol, which afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH3:11])[CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Product: CN(CC[C@H]1CC[C@H](/C=C/CN2CCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-methyl-{2-[4-(3-pyrrolidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester as yellow viscous oil, MS: 405 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])[CH3:3].[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>N1C=CC=CC=1.C(Cl)Cl>[C:2]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][O:11][S:13]([CH3:16])(=[O:15])=[O:14])=[O:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Hydroxyethyl)methylcarbamic acid 1,1-dimethylethyl ester (350 mg, 2.0 mmol) was dissolved in pyridine (2 ml). Mesyl chloride (0.229 ml, 2.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over MgSO4 and concentrated under reduced pressure to give methanesulfonic acid 2-(tert-butoxycarbonyl-methyl-amino)-ethyl ester. This was used in the next reaction without complete purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:7]2[CH2:8][CH2:9][C@@H:10]([CH3:12])[CH2:11][C@H:6]2[O:5][CH2:4][S:3]1.C([Li])CCC.[CH3:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[OH:25][C@@:20]([C@H:4]1[S:3][C:2]([CH3:13])([CH3:1])[C@@H:7]2[CH2:8][CH2:9][C@@H:10]([CH3:12])[CH2:11][C@H:6]2[O:5]1)([CH2:21][CH2:22][CH2:23][CH3:24])[CH3:19]
Reactant: C[C@@H]1CC[C@@H]2[C@@H](C1)OCSC2(C)C
Reactant: CCCCC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@@](C)(O)[C@@H]1O[C@@H]2C[C@H](C)CC[C@H]2C(C)(C)S1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
A vigorously stirred solution of (4aR,7R,8aR)-hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin (9 g, 0.045 mole, prepared as described by ELIEL et al. Org. Synth. 65, 215 [1987]) in 130 ml of anhydrous tetrahydrofuran was cooled to -78° C. under an ar8on atmosphere and butyllithium (3.168 g, 0.0195 mole) dissolved in 32 ml of hexane was added dropwise over a period of 15 minutes. The solution was further stirred for additional 15 minutes. The temperature of the solution was allowed to slowly reach 0° C. and further stirred for 15 minutes. The solution was cooled again to -78° C. under the argon atmosphere, the stirring was continued and 2-hexanone (4.5 g, 0.045 mole) dissolved in 25 ml of anhydrous tetrahydrofuran was added dropwise over a period of 20 minutes. The solution was further stirred for additional 4 hours. The temperature of the solution was allowed to slowly reach the room temperature, 10 ml of water were added dropwise over a period of 10 minutes and then 15 ml of a saturated solution of ammonium chloride in water were added at once. The reaction mixture was S partitioned between diethyl ether and water. The ether portion was washed with brine, dried over anhydrous Na2SO4 which was then removed by filtration, and evaporated to leave 13.1 g of a thick syrup. This thick syrup was dissolved in 10 ml of hexane-ethyl acetate (9:1 v:v) solvent and chromatographed on 1000 g of silica gel (230-400 mesh ASTM). The 5 liters of hexane-ethyl acetate that were eluted, were evaporated in vacuo to leave a viscous colorless liquid residue. This liquid was distilled at reduced pressure. The fraction distilling at 95°-97° C. and 0.05 Torr was collected yielding 6.2 g (45.9%) of the title compound, which shows [α]365 =-28.91° (C=1.61 in CHCl3). Anal. Calcd. for C17H32O2S: C,67.96; H,10.74; O,10.65; S,10.65, Found: C,68.20; H,10.63; O,10.47; S,10.56.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16]([C:18]3[C:19](=[O:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30][CH3:31])=[O:29])[CH:23]=3)(O)[C:11]3[N:12]=[C:13]([CH3:15])[S:14][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:37]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:18]3[C:19](=[O:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30][CH3:31])=[O:29])[CH:23]=3)[C:11]3[N:12]=[C:13]([CH3:15])[S:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:37]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)CCc1sc(C)nc1C2(O)c1cn(Cc2cccc(C(=O)OC)c2)c(=O)[nH]c1=O
Solvent: CC(=O)O
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(Cc2cccc(C(=O)OC)c2)c(=O)[nH]c1=O

Procedure:
A solution of the product from step (iv) (0.18 g) in glacial acetic acid (6 ml) was stirred at 100° C. for 2 hours. The solution was evaporated to dryness (azeotroped twice with toluene) and the residue purified by chromatography eluting with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[S:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Temperature: 25 °C
Yield: 68.18 %

Procedure:
To a solution of ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in J. Chem. Soc. Perkin Trans-1: Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 2.0 g (6.36 mmol) in a mixture of toluene:water (35:2 ml) was added (4-chlorophenyl)boronic acid [0.99 g, 6.36 mmol] and potassium carbonate (1.76 g, 12.73 mmol) at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.31 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100° C. for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite and the celite cake was washed with ethyl acetate (50 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using and 6% ethyl acetate in hexanes as an eluent to obtain the title compound (1.5 g, 68.18%).
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)C>[NH2:7][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([C:21]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[CH3:11])[CH:8]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Nc1cc(Br)c(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc(N)c(F)cc2F)c(C)c1

Procedure:
5-bromo-2,4-difluoroaniline (500 mg, 2.40 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (INTERMEDIATE 16, 797 mg, 2.88 mmol), sodium carbonate (2.40 mL, aq., 2M, 2.88 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (196 mg, 0.24 mmol) and ethanol (15 ml) were heated in an 80° C. oil bath for 3 hours then allowed to cool to ambient overnight. Volatiles were removed under reduced pressure. The pot residue was worked up w/DCM /brine/Na2SO4/filtration/concentration to afford a dark oil. The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by a 0% to 40% EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=277.09; found=278.03 (M+1)+.
Reaction SMILES: [CH:1]1([C@H:4]([NH2:26])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C(O)C>O1CCOCC1>[CH:1]1([C@H:4]([NH:26][CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: C=CC(=O)OC
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)CCN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Temperature: 85 °C

Procedure:
A solution of {(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amine (16-7, 100 mg, 0.282 mmol, 1 equiv) and methyl acrylate (0.076 mL, 0.85 mmol, 3.0 equiv) in a 1:1 mixture of ethanol and dioxane (10 mL) was heated at 85° C. for 20 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography (100% EtOAc) to provide methyl N-{(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}-β-alaninate (41-1) as a colorless oil that solidified to a white solid over time. LRMS m/z (M+H) 441.4 found, 441.2 required.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=[C:17]([NH2:27])[N:16]=1>>[NH2:27][C:17]1[N:16]=[C:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(N2CCOCC2)n1
Product: Nc1nc(-c2cc(F)c(C=O)c(F)c2)cc(N2CCOCC2)n1
Yield: 68 %

Procedure:
The title compound was prepared following the General Procedure A using: (3,5-difluoro-4-formylphenyl)boronic acid (2.17 g, 11.7 mmol) and 4-chloro-6-(4-morpholinyl)-2-pyrimidinamine (2.50 g, 11.7 mmol). The solid was dry loaded in 10 g of SiO2. Flash chromatography on SiO2 eluting from 100% CHCl3 to 90:10 CHCl3:CH3OH afforded the title compound (2.55 g, 51%) as a yellow solid. LC-MS (ES) m/z=321 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[S:24][C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl>C(O)(C)C.O>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH2:12][N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[CH:14][NH:15]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 90 °C
Yield: 334.2 %

Procedure:
To a solution of 1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (410 mg, 0.094 mmol) in isopropanol (10 mL) was added aqueous KOH (2 M, 53 mg, 0.42 mL, 0.94 mmol) and the resulting solution was heated (90° C., 24 h). The reaction mixture was diluted with H2O (10 mL) and neutralized with aqueous 1 M HCl. The suspension was filtered and the solid was washed with EtOAc (20 mL) and dried in vacuo to provide the title compound as a tan solid (128 mg, 33%). MS (ESI): mass calcd. for C22H21N3O3S, 407.4; m/z found, 408.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 11.18 (5, 1H), 7.88 (d, J=9.7, 1H), 7.73 (d, J=10.8, 1H), 7.68 (d, J=10.0, 1H), 7.44-7.40 (m, 2H), 7.35-7.28 (m, 2H), 7.06-7.03 (m, 1H), 3.66 (5, 2H), 2.88-2.84 (m, 2H), 2.22-2.16 (m, 1H), 2.04-2.00 (m, 2H), 1.80-1.77 (m, 2H), 1.58-1.55 (m, 2H), the CO2H proton was not detected.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C1(C)C=C(C)C=C(C)C=1.[C-]#N.[Na+].[Cu][C:27]#[N:28].[I-].[Na+].C(N1C=CN=C1)CCC>O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:27]#[N:28])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: N#C[Cu]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: CCCCn1ccnc1
Agent: [C-]#N
Agent: [I-]
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (99% purity, 5.0 g, 0.02 mol) and mesitylene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and sodium cyanide powder (CyPlus®, 1.40 g, 0.027 mol, assuming 95% purity), copper(I) cyanide (0.27 g, 0.003 mol, 99% purity), sodium iodide (0.45 g, 0.003 mol, 99% purity) and 1-butyl-1H-imidazole (1.9 g, 0.015 mol, 98% purity) were added. The mixture was heated at reflux (about 167-168° C.) for 6 h and then allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 1 h, the reaction mixture was filtered, and the solid collected was washed successively with water (3×10 mL), mesitylene (10 mL) and dried to a constant weight in a vacuum-oven at 55° C. to give the title compound as a light yellow solid (3.4 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:5][CH:4]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH3:2]
Reactant: CCC1CC(CO)CC1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCC1CC(COS(C)(=O)=O)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (0.220 g, 0.964 mmol) in DCM (5 mL) was added TEA (0.16 mL, 1.15 mmol) and methanesulfonyl chloride (0.083 mL, 1.06 mmol) at about 0° C. The reaction mixture was allowed to warm to about 25° C. and stirred at about 25° C. for about 16 h. The reaction mixture was partitioned between water (20 mL) and DCM (20 mL). The aqueous solution was washed with DCM (2×20 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give tert-butyl 2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295 g, 100%): LC/MS (Table 1, Method b) Rt=2.55 min; MS m/z: 307 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[NH2:21]Cl.O>CN(C=O)C.CCOCC>[NH2:21][N:8]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc(C(C)C)[nH]c1C(=O)OCC
Reactant: NCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc(C(C)C)n(N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1B (2.53 g, 10 mmol) in dry DMF (40 ml) was added NaH (60%, 550 mg, 13.75 mmol) in one portion. After H2 evolution subsided, NH2Cl in ether (85 ml) was added dropwise via additional funnel. The reaction mixture was stirred at room temperature for 1 h. Water was added, the mixture was extracted with ether (×3), the combined ether layers were washed with brine, dried over MgSO4, concentrated in vacuo to give 1C (2.50 g, 93%) as an oil. Compound 1C had an analytical HPLC retention time=2.893 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=269+.