Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH2:27])=[O:26])[N:6]=1)[CH2:3][OH:4].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>>[OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH2:27])=[O:26])[N:6]=1)[CH2:3][OH:4]
Reactant: NC(=O)c1nc(-c2ccc(Oc3ccc(F)cc3)cc2)cc([C@@H](O)CO)n1
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Product: NC(=O)c1nc(-c2ccc(Oc3ccc(F)cc3)cc2)cc([C@H](O)CO)n1

Procedure:
(S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide (Compound Example No. 21) was prepared in a similar fashion to (R)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxamide (Compound Example No. 20) using AD-Mix-α instead of AD-Mix-β. 1H NMR (400 MHz, CD3OD): 8.25 (2H, d, J=8.8 Hz), 8.09 (1H, s), 7.09-6.98 (6H, m), 4.75 (1H, m), 4.10 (1H, dd, J=3.6, 12 Hz), 3.77 (1H, dd, J=5.2, 12 Hz); LC/MS: m/z=370[M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 2-bromo-1-(2,4-dichlorophenyl)ethanone (7.09 g, 26.5 mmol) and potassium thiocyanate (2.57 g, 26.5 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 5.97 g (91.7%) of the desired product as a solid.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](=[O:27])(=[O:26])[NH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:27])=[O:26])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 3-methyl-4-(6-(N-(pyrimidin-4-yl)sulfamoyl)isoquinolin-1-yl)piperazine-1-carboxylate (0.043 g, 0.089 mmol) was dissolved in DCM (0.887 ml) and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for one hour at room temperature. The reaction was concentrated, triturated with ether, and filtered. The solids were washed with ether and vacuum dried to afford 1-(2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate as a yellow solid. (ESI) 385.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[S:10][C:11]2[N:12]=[C:13]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[CH2:33][CH3:34])[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:16]=2[N:17]=1.[C:36](O)(=[O:40])[C@H:37]([CH3:39])[OH:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([C:25]1[N:24]([C:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:16]3[N:17]=[C:9]([CH2:8][N:3]4[CH2:4][CH2:5][N:6]([C:36](=[O:40])[C@@H:37]([OH:38])[CH3:39])[CH2:7][C:2]4([CH3:35])[CH3:1])[S:10][C:11]=3[N:12]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNCC3(C)C)sc2n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)[C@H](C)O)CC3(C)C)sc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2,2-dimethylpiperazin-1-ylmethyl)-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (200 mg, 0.41 mmol), L-lactic acid (34 μL, 85% solution in H2O), HATU (170 mg, 0.45 mmol) and DIPEA (80 μL, 0.46 mmol) in DCM (4 mL) was allowed to stir at r.t. for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-2%) then (C18, MeOH:H2O, 10-20%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 829 (41 mg, 18%). LCMS (method I): RT 3.79 min, [M+H]+ 565.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.98 (1 H, m), 7.76-7.75 (1 H, m), 7.32-7.22 (2 H,m), 4.41-4.38 (5 H, m), 4.08-4.01 (1 H, m), 3.89-3.88 (5 H, m), 3.79-3.77 (1 H, m), 3.59-3.44 (2 H, m), 3.34 (2 H, q, J=7.47 Hz), 3.27-3.25 (1 H, m), 2.75 (2 H, s), 1.44 (3 H, t, J=7.47 Hz), 1.37-1.35 (3 H, m), 1.27-1.11 (6 H, m)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:22])[NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])[C:15]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:22]
Reactant: CN(C)CCNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-5-(2-dimethylamino-ethylcarbamoyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester (120 mg, 0.3 mmol) and TFA (1 mL) in CH2Cl2. MS (LC-MS): 274.0 [M]+; tR (HPLC conditions c): 2.17 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[C:31]([O:33]COC)[CH:30]=[CH:29][C:10]=1[C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:10]=1[C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)c(OCc2ccccc2)c1
Agent: Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Oc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)c(OCc2ccccc2)c1
Temperature: 50 °C
Yield: 85.7 %

Procedure:
To a solution of 2′,7-dibenzyloxy-4′-methoxymethyloxy-isoflav-3-ene (0.480 g, 1 mmol) in acetonitrile:water (20 mL:1 mL) was added triphenyl phosphine hydrobromide (0.788 g, 2 mmol). The reaction was heated to 50° C. for ca. 2 hrs. After disappearance of the starting material (TLC), the solvent was evaporated at 20° C. The residue was extracted with EtOAc:water (3×10 mL:10 mL). The organic layers were combined, dried and evaporated. The residue was chromatographed over silica using hexanes:EtOAc (5:1). The organic fractions were evaporated to provide 0.374 g (78%) of product as an oil. Because of the instability of this intermediate, it was immediately used for the next step: TLC Rf0.43, in hexanes:EtOAc (5:1); 1H NMR (600 MHz, DMSO-d6) δ 9.66 (s, 1H, OH), 7.46-7.32 (m, 10H, 2×CH5), 7.14, 7.13 (d, 1H, J=8.4 Hz, Ar—H5), 7.01-6.99 (d, 1H, J=7.8 Hz, Ar—H6′) 6.57-6.55 (m, 2H, H4/Ar—H5′), 6.59-6.52 (d, 1H, J=2.4 Hz, Ar—H8), 6.48-6.47 (d, 1H, J=2.4 Hz, Ar—H3′), 6.41-6.39 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5′), 5.07 (s, 4H, PhCH2), 4.85 (s, 2H, H2).
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:13]N1[C:18](=O)[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].O=O>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1([OH:24])[CH2:16][CH2:23][CH2:22][CH2:21][CH2:20][CH2:17][CH2:18][CH2:3][CH2:2][CH2:1][CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1CCCCCCCCCCC1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCCCCCCCCC1
Product: OC1CCCCCCCCCCC1
Yield: 2.9 %
Yield: 9.8 %

Procedure:
In a flask having an inner volume of 100 ml, 8.4 g (50 mmol) of cyclododecane, 12.6 g of acetic acid, 32.6 mg (0.2 mmol) of N-hydroxyphthalimide, 57.8 mg (0.2 mmol) of bis(acetylacetonato)manganese(II) dihydrate, and 4.0 mg (0.02 mmol) of cobalt(II) acetate tetrahydrate were placed, and an oxygen balloon was attached to the reactor. The liquid temperature was raised on an oil bath and was held at 100° C. The reaction was terminated by cooling 4 hours later. A reaction mixture was diluted with 60 g of acetic acid to thereby dissolve all of solid matters. The resulting solution was analyzed to find that a conversion from cyclododecane was 16.1% and a selectivity for dodecanedioic acid was 27.5%. In addition, cyclododecanone (selectivity: 2.9%) and cyclododecanol (selectivity: 9.8%) were by-produced.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([O:21][C:22]([NH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:23])[NH:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29](=[CH:7][C:6]3[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=3)[C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NC(=O)OC(C)(C)C)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-tert-butyloxycarbonylamino-2-oxindole to give 0.35 g of [3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-carbamic acid tert-butyl ester as a yellow-orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Product: FC(F)(F)c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, off-white solid (72 mg, 56%), MS (ISP) m/z=439.5 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (intermediate M) (0.1 g, 0.29 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.12 g, 0.38 mmol).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)(O)[O-].[Na+]>CCCCCC>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: COC(=O)CNc1ccc(Oc2ccccc2)cc1
Reaction time: 24 h
Yield: 32.6 %

Procedure:
A mixture of 4-phenoxyaniline (30 g, 0.162 mol), methyl chloroacetate (21.3 ml, 0.243 mol) and sodium bicarbonate (27.2 g, 0.324 mol) was heated at 100°-120° C. with magnetic stirring for 24 hours. The resulting semi-solid was partitioned between dichloromethane (300 ml) and water (300 ml) then separated. The aqueous layer was extracted with dichloromethane (200 ml) and the organic extracts were combined. The extracts were washed with 2N hydrochloric acid (2×200 ml) and water (2×200 ml), dried (MgSO4) and evaporated to give a brown oil. This was heated with hexane (300 ml) to give an oil suspension. The hexane was decanted off and residual oil crystallised on cooling. The solid was triturated with ether/hexane 1:1 and filtered to give a brown solid (13.6 g, 33%) m.p. 80°-82° C. A second crop of a pale yellow solid was also given (10.5 g, 25%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:10]1([CH:9]=[N:16][OH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: ON=CC1(Cl)C=CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-chlorosuccinimide (4.63 g, 34.7 mmol) was added to a solution of benzaldehyde oxime (3.5 g, 28.9 mmol) in DMF (30 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred for 3 h at RT, mixed with water (100 ml) while being cooled with ice and extracted with ether (3×100 ml). The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethylbenzene (C) was obtained as a yellowish solid (4.28 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O.[H-].[Na+]>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[CH:9][C:3]([C:1]#[N:2])=[C:4]([OH:5])[N:6]=2)=[CH:14][CH:15]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(F)cc2)nc1O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
2-Cyanoacetamide (4.31 g) and 3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (9.00 g) were added in this order to a mixture of sodium hydride (60% oil, 4.10 g) and DMF (90 mL), and the resultant mixture was stirred at 105° C. for 2 hours. The solvent was distilled off. Water was added to the obtained residue, and then, the mixture was rendered acidic by the addition of acetic acid and stirred at 70° C. for 15 minutes. Methanol was added to the reaction mixture for suspension, and the deposited solid was washed with ethyl acetate to obtain the title compound (9.98 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@@H:19]1[CH2:23][C@H:22]([OH:24])[C@H:21]([CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C@H:20]1[CH2:41][OH:42])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[CH2:23][C:22](=[O:24])[C@H:21]([CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C@H:20]1[CH:41]=[O:42])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCC/C=C\C[C@@H]1[C@@H](CO)[C@H](OCc2ccccc2)C[C@@H]1O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1[C@H](OCc2ccccc2)CC(=O)[C@@H]1C/C=C\CCCC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To a solution of oxalyl chloride (68.4 mmoL) in dichloromethane (10 volumes) at −78° C. was added DMSO (114.0 mmoL). The solution was stirred at −78° C. for 30-60 minutes followed by drop-wise addition of (5Z)-benzyl 7-[(1R,2S,3R,5S)-3-benzyloxy-5-hydroxy-2-(hydroxymethyl)cyclopentyl]hept-5-enoate (16, R1 is phenyl, R2 and R3 are H and R7 is benzyl, 10 g, 22.8 mmoL) in dichloromethane (10 volumes). The reaction mixture was stirred at −78° C. for 30 minutes at which time triethylamine (105.9 mmoL) was charged. The mixture was stirred at −78 to −60° C. for 4-6 hours followed by quenching with saturated aqueous ammonium chloride (10 volumes). The mixture was warmed to 0° C. The layers were separated; the organic layer was washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered through Celite® and concentrated to dryness. The residue was purified by column chromatography (50% ethyl acetate in heptanes) to yield (5Z)-benzyl 7-[(1R,2R,3R)-3-benzyloxy-2-formyl-5-oxocyclopentyl]hept-5-enoate (17, R1 is phenyl, R2 and R3 are H and R7 is benzyl) as an oil (9.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16](Cl)=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.[Li][C:26]#[N:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:16]([C:26]#[N:27])=[C:15]([C:18]#[N:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: [Li]C#N
Reactant: C#CCOc1cc(-n2c(Cl)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Temperature: 120 °C
Yield: 45.1 %

Procedure:
The product of Example 2, 1-(4-chloro-2-fluoro5-propargyloxyphenyl)-5-chloro-4-cyano-3-propyl-1,3-dihydro-2H-imidazol-2-one (V) (0.25 g, 0.68 mmol), was stirred in 10 mL dimethylformamide (DMF). To this mixture was added LiCN (2 mL of 0.5M in DMF, 1 mmol) and the resulting mixture was heated to 120° C. for 15 minutes. The mixture was cooled poured onto water, extracted with ethyl acetate, dried, concentrated and eluted through silica gel (50:50 ethyl acetate:hexane) to give 0.11 g of 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4,5-dicyano-3-propyl-1,3-dihydro-2H-imidazol-2-one (VI) (m.p. 76° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:23]=2)[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:28]([C:27]2[C:22]([CH:19]3[CH2:21][CH2:20]3)=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-(2-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Cl.COC(OC)CNC.[CH3:10][O:11][C:12]1[C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=[CH:16][C:13]=1[CH:14]=O>[Pd].COC1C2OCOC=2C=CC=1C=O.C(O)C>[CH3:10][O:11][C:12]1[C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=[CH:16][C:13]=1[CH3:14]
Reactant: COc1c(C=O)ccc2c1OCO2
Agent: [Pd]
Agent: CNCC(OC)OC
Agent: Cl
Solvent: CCO
Product: COc1c(C)ccc2c1OCO2
Yield: 8.2 %

Procedure:
To 100 ml of ethanol, were charged 0.18 ml of ethanol containing 22.2 g of hydrochloric acid dissolved therein, 0.79 g of N-methylaminoacetaldehyde dimethylacetal, 1.0 g of 2-methoxy-3,4-methylenedioxybenzaldehyde, 0.12 g of 5% palladium on carbon catalyst and 10 ml of ethanol, and hydrogenation was carried out in an oil bath at 70° C. for 2 hours. The amount of hydrogen absorption was 100% of the theoretical amount. After the reaction was over, the catalyst was filtered out and 2N NaOH aqueous solution was added to the reaction mixture to make the filtrate alkaline (pH 11). The resulting mixture was then extracted with ethyl acetate. The liquid extract was analyzed by GC and LC to show 1.32 g of 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal (yield 84%), 0.02 g of 2-methoxy-3,4-methylene-dioxybenzylalcohol (yield 2%), 0.076 g of 2-methoxy-3,4-methylenedioxytoluene (yield 8%) and 0.007 g of 2-methoxy-3,4-methylenedioxybenzaldehyde of the starting material (conversion rate:99%). The selectivity to the desired 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal was 98%.
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[C:21]([CH2:33][CH2:34][CH3:35])([CH2:30][CH2:31][CH3:32])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH3:35])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][C:11]=2[S:16](=[O:17])(=[O:18])[N:15]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A suspension of the compound of Example 2F (110 mg, 0.21 mmol) in 1:1:1 tetrahydrofuran-ethyl acetate-methanol (20 mL) was treated with 10% palladium on carbon (30 mg) and stirred at 25° C. under hydrogen atmosphere for 18 hours. The mixture was filtered through celite® and the filtrate concentrated in vacuo to afford the title compound (86 mg, 94%). 1H NMR (300 MHz, DMSO-d6): δ 13.87 (m, 1 H), 10.33 (s, 2 H), 8.15 (d, J=7.72 Hz, 1 H), 7.72 (m, 2 H), 7.52 (m, 2 H), 7.16 (m, 2 H), 2.15 (m, 2 H), 1.97 (m, J=11.77 Hz, 2 H), 0.89 (m, 2 H), 0.60 (m, 8 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][NH:23]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][N:23]2[C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc2ccccc2[nH]1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a 0° C. suspension of indole-2-carbonyl chloride (100 mg, 0.56 mmol) in CH2Cl2 was added a solution of TEA (235 μL, 1.67 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (156 mg, 0.84 mmol) in CH2Cl2. After 1.5 h at 0° C., the mixture was diluted with saturated aqueous (satd. aq.) NaHCO3 and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with satd. aq. NaCl (20 mL), dried (Na2SO4), and concentrated to give a yellow liquid, which was purified by FCC to give a yellow solid (130 mg, 46%). 1H NMR (CDCl3): 9.37-9.17 (m, 1H), 7.70-7.64 (m, 1H), 7.47-7.41 (m, 1H), 7.35-7.28 (m, 1H), 7.19-7.10 (m, 1H), 6.86-6.78 (m, 1H), 5.13 (s, 1H), 4.77-4.50 (m, 1H), 4.02-3.80 (m, 1H), 3.80-3.39 (m, 2H), 2.08-1.88 (m, 2H), 1.54-1.35 (m, 9H).