Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:38]=2)=[CH:33][CH:32]=1)([C:7]1[N:8]=[CH:9][N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1)[CH2:3]C(C)C.Cl>[C].[Pd]>[OH:1][C:2]([C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:38]=2)=[CH:35][CH:36]=1)([C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)[CH2:3][CH:2]([CH2:7][CH3:11])[CH3:3]
Reactant: CC(=O)Nc1cccc(-c2ccc(C(O)(CC(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c1
Agent: [Pd]
Agent: Cl
Product: CCC(C)CC(O)(c1ccc(-c2cccc(NC(C)=O)c2)cc1)c1c[nH]cn1
Yield: 34.5 %

Procedure:
By the reaction in the same manner as in Example 41-(ii) using N-[4′-[1-hydroxy-3-methyl-1-(1-trityl-1H-imidazol-4-yl)butyl][1,1′-biphenyl]-3-yl]acetamide (1.31 g), 10% palladium carbon (386 mg) and 1N hydrochloric acid (0.637 ml), the colorless amorphous title compound (141 mg) was obtained.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]([OH:13])[CH2:11]O)[CH3:7].C(N(CC)CC)C.C[O-].[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH2:6]([N:8]([CH2:9][CH:10]1[CH2:11][O:13]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:7]
Reactant: CCN(CC(O)CO)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC1CO1)c1ccccc1
Temperature: 0 °C
Yield: 44.9 %

Procedure:
Methanesulfonyl chloride (2.5 mL, 1.5 eq.) was added to a solution 3-(ethyl-phenyl-amino)-propane-1,2-diol (4.22 g, 21.6 mmol) and triethylamine (9.03 mL, 3.0 eq.) in dichloromethane (20 mL) at −30 to −35° C. and the resulting mixture was stirred and warmed to 0° C. The reaction was quenched by sat. NaHCO3 (30 mL) and the separated aqueous phase was extracted with 2×20 mL CH2Cl2 and 20 mL EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH (30 mL) and treated with NaOMe (2.3 g, 2.0 eq.) at 65-70° C. for 3 h. After cooling to room temperature, the mixture was diluted with sat. NaHCO3 (50 mL) and extracted with 3×30 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated and the product was purified by chromatography (10% EtOAc/hexanes) to give ethyl-oxiranylmethyl-phenyl-amine (1.72 g, 45%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:19]#[N:20])=[CH:9][N:8]=1)(=O)=O.[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O.C1COCC1>C(Cl)Cl>[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]#[N:20])=[CH:9][N:8]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: N#Cc1cnc(OS(=O)(=O)C(F)(F)F)c(-c2ccccc2)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cnc(-c2ccc(C=O)cc2)c(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-cyano-3-phenylpyridin-2-yl trifluoromethanesulfonate (1-2) (328 mg, 1.0 mmol), 4-formylphenylboronic acid (225 mg, 1.5 mmol), Pd(dppf)(CH2Cl2) (16 mg, 0.02 mmol), 2 M of Cs2CO3 water solution (2 mL, 4 mmol), and THF (2 mL) was microwaved (Smith-Synthesizer) at 160° C. for 10 min. After cooled to rt, the reaction mixture was treated with DCM (40 mL) and washed with water, brine and dried over anhydrous Na2SO4. Filtration and concentration afforded the crude product which was purified by flash chromatography on silica gel to give pure 6-(4-formylphenyl)-5-phenylnicotinonitrile (1-3). Analytical LCMS: single peak (214 nm), 3.240 min. 1H NMR (500 MHz, CDCl3): δ 10.01 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.31-7.39 (m, 3H), 7.13-7.18 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]4[S:22][C:23]([C:25]([CH:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])=[CH:24][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>>[OH:26][CH:25]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:23]1[S:22][C:19]2[C:20](=[O:21])[N:15]([C:12]3[CH:11]=[CH:10][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:14][CH:13]=3)[CH:16]=[N:17][C:18]=2[CH:24]=1
Reactant: CN1CCCN(c2ccc(-n3cnc4cc(C(=O)C5CCOCC5)sc4c3=O)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCCN(c2ccc(-n3cnc4cc(C(O)C5CCOCC5)sc4c3=O)cc2)CC1

Procedure:
3-[4-(4-Methyl[1,4]diazepan-1-yl)phenyl]-6-(tetrahydropyran-4-carbonyl)-3H-thieno[3,2-d]pyrimidin-4-one and sodium borohydride were reacted by method Y. The product with the molecular weight of 454.60 (C24H30N4O3S) was obtained in this way; MS (ESI): 455 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([CH2:13][CH3:14])[C:5]2[CH:15]=[N:16][CH:17]=[CH:18][C:4]1=2)[CH3:2].C(N1CCN(C(=O)C)C2C=CN=CC1=2)(=[O:21])C.N1C=CN=C2C=NC=CC=12.CN1CCN(C)C2C=NC=CC1=2>CCOC(C)=O.CCN(CC)CC>[CH2:1]([N:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([C:13](=[O:21])[CH3:14])[C:5]2[CH:15]=[N:16][CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Reactant: CCN1c2ccncc2N(CC)C2CCCCC21
Agent: CN1CCN(C)c2cnccc21
Agent: c1cc2nccnc2cn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN1c2ccncc2N(C(C)=O)C2CCCCC21

Procedure:
29 (0.250 g, 1.15 mmol) and 10 ml of THF were placed in a 100 ml Schlenk flask. The solution was cooled to −78° C., 0.51 ml of n-BuLi (1.27 mmol, 1.1 eq; 2.5 M in hexane) were added and the reaction solution was stirred without cooling for 30 minutes. After 30 minutes, the reaction solution was cooled back down to −78° C. and 0.09 ml (0.109 g, 1.4 mmol, ρ=1.1051 g/ml) of acetyl chloride were added, the cooling bath was removed and the mixture was stirred without cooling for 1 hour. The reaction was subsequently stopped by means of 4 ml and extracted three times with 20 ml of DCM. The combined organic phases were dried over Na2SO4 and the solvent was distilled off on a rotary evaporator. The crude product was purified on silica gel (EtOAc/MeOH, 10:2) to give 48 mg (0.18 mmol, 16%) of a colorless solid. Rf=0.16 (EtOAc/NEt3, 10:1). 1H NMR: (300 MHz, CDCl3): δ=1.19 (t, 3J=7.2 Hz, 3H, H3C—CH2—N-5), 1.24 (m, 2H), 1.45 (m, 2H), 1.58 (m, 2H), 1.74 (m, 1H), 2.18 (m, 1H), 3.34 (m, 2J=14.4 Hz, 3J=7.2 Hz, 1H, H3C—CHAB—N-5), 3.53 (m, 1H, C—H), 3.57 (m, 2J=15.2 Hz, 3J=7.2 Hz, 1H, H3C—CHAB—N-5), 4.90 (bs, 1H, C—H), 6.62 (d, 3J=5.6 Hz, 1H, H-4), 8.12 (s, 1H, H-1), 8.08 (d, 3J=5.6 Hz, 1H, H-3). 13C NMR (100 MHz, CDCl3): δ=12.4 (H3C—CH2—N-5), 18.9 (C-7), 22.8 (H3C—CO—N-10), 24.7 (C-8), 25.8 (C-6), 28.5 (C-9), 40.0 (H3C—CH2—N-5), 48.7 (C-9a), 53.7 (C-5a), (C-4), 106.4 (C-4), 120.1 (Cq, C-10a), 145.1, 145.2 (C-1, Cq, C-4a), 147.1 (C-3), 167.1 (C═O) ppm. GC-MS (EI): RT 10.39 min, m/e (%) 260 (11), 259 (M+, 100), 230 (8), 218 (9), 217 (79), 216 (40), 203 (4), 202 (23), 203 (3), 202 (23), 201 (4), 189 (6), 188 (31), 187 (4), 186 (3), 174 (11), 162 (4), 161 (6), 160 (5), 158 (4), 148 (5), 146 (6), 136 (3), 132 (4), 131 (12), 120 (6), 43 (3); IR (neat): ν=3398 (s), 2933 (s), 2863 (m), 1731 (m), 1637 (vs), 1595 (vs), 1512 (s), 1546 (w), 1449 (m), 1397 (s), 1365 (s), 1334 (m), 1285 (s), 1239. (m), 1198 (m), 1168 (vs), 1123 (w), 1067 (w), 1068 (w), 1016 (w), 802 (vs), 718 (w), 668 (m). HRMS (EI): calculated for C15H21N3O 259.1685 [M+], found: 259.1687.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:8][C:9]=1[CH2:10][CH2:11][CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:10]([C:9]1[S:8][C:7]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=2)=[N:6][C:5]=1[CH2:4][CH2:3][OH:2])[CH2:11][CH3:12]
Reactant: CCCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Temperature: 0 °C
Yield: 75.2 %

Procedure:
[[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester (8.66 g, 24.2 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (100 mL) and then cooled to 0° C. with stirring. Lithium aluminum hydride (24.2 mL, 1M in ThF, 24.2 mmol) is slowly added by syringe and the reaction is monitored by TLC. Upon complete conversion, the reaction is carefully quenched using water, base, and water. Celite is added to the reaction, followed by diethyl ether and the mixture is then filtered through a celite plug. The two phases are then separated and the organic layer is washed using water and brine. The organic layer is the dried over anhydrous sodium sulfate and concentrated. The pure 2-[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (5.739 g, 18.2 mmol) is obtained in 75% yield after flash column chromatography.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH2:22]([O:21][C:19]([C:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCC(CC)(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(Cc1ccc(C(=O)O)s1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(2-Benzyloxycarbonyl-2-ethyl-butyl)thiophene-2-carboxylic acid tert-butyl ester (24.9 g, 61.9 mmol) was added trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give the title compound (quantitative)
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#[N:14]>C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([C:1](=[O:3])[CH3:2])[C:13]#[N:14]
Reactant: CCO
Reactant: N#CCc1ccccc1Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC(=O)C(C#N)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The procedure of P. L. Julian et al (Org. Syn, C. V. II, p, 487) was used. To 25 mL of anhydrous ethanol was added 2.0 g or sodium metal. The mixture was heated to 100° C. with a heating mantle to effect complete reaction. To the warm solution was added 10.0 g 2-chlorophenylacetonitrile followed by 9.7 mL dry ethyl acetate. After one hour, the mixture was cooled to -10° C. and was filtered through a medium fritted funnel. The white precipitate was washed twice with ether and was combined with the first batch. The solid material was dissolved in 75 mL water. To this was added 5 mL acetic acid. The mixture was then extracted three times with ether. The combined organic material was dried over sodium sulfate, stripped of solvent in vacuo, and was restripped from toluene to give the title compound sufficiently pure for the the next reaction. Rf 0.14 in 20% ethyl acetate/hexane.
Reaction SMILES: O([Si:4]([O:7][CH2:8][CH3:9])([CH3:6])[CH3:5])CC.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>CCOCC>[CH2:12]([CH2:9][CH2:8][O:7][SiH:4]([CH3:5])[CH3:6])[CH:11]=[CH2:10]
Reactant: C=CC[Mg]Br
Reactant: CCO[Si](C)(C)OCC
Solvent: CCOCC
Product: C=CCCCO[SiH](C)C
Temperature: -20 °C
Yield: 84 %

Procedure:
In a 1000 ml flame-dried flask equipped with a magnetic stir bar, 250 ml of dry ether and 37 g (250 mmol) of diethoxyldimethylsilane were injected under argon. The solution was vigorously stirred while 250 ml of allylmagnesiumbromide in ether (1.0 M) was added dropewise over 2 hours. The solution was refluxed overnight to complete the coupling reaction. After cooling the mixture to −20° C. and removing the solid by filtration, the solvent was removed by rovaperation. The raw product was subjected to vacuum distillation to obtain 30 g of pure allylethoxyldimethylsilane (colorless liquid) with yield of 84%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C@H:18]3[CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[CH2:58][CH2:57][N:49]2[C:50]3[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=3[CH:56]=[C:48]2[C:47]1=[O:59])(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[CH:32][C:33]([F:45])=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C@H:18]3[CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: C[C@@H]1CN(C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)C[C@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of 109e (400 mg, 1.0 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (490 mg, 1.0 mmol), PdCl2(dppf) (80 mg, 0.1 mmol), 2.0 M Na2CO3 (2.0 equiv) in DMF (4 mL) was heated at 100° C. for 2 h. Brine was added and the mixture was extracted with EA (50 mL) three times. The combined organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 30:1 DCM/MeOH to afford 109f as a brown solid (354 mg, 52%). LCMS: [M+H]+ 668
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH2:12]([N:14]([CH2:23][CH3:24])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH3:13].O>C1C=CC=CC=1>[CH2:23]([N:14]([CH2:12][CH3:13])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[O:20][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:17][CH:16]=1)[CH3:24]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CC1(C)N=C1c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)c1ccc(C2OC(C)(C)N=C2c2ccccc2)cc1
Yield: 38.3 %

Procedure:
4 g of 2,2-dimethyl-3-phenyl-2H-azirine and 5 g of 4-diethylaminobenzaldehyde were exposed to light in 350 ml of benzene at 230° C. for 4 hours under an atmosphere of argon with a mercury high-pressure lamp of 150 watt in a water-cooled ring-mantle vessel through a 3 mm thick filter of Pyrex glass. After removing the solvent in a water-jet vacuum, the residue was crystallized from n-hexane/acetone and then a second time from n-pentane/acetone. The crystalline product was then dried at 60° C. in the water-jet vacuum, and there were obtained 3,4 g of 5-[p-(diethylamino)-phenyl]-2,2-dimethyl-4-phenyl-3-oxazoline having a melting point of 104°-105° C.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH2:18])[CH2:4][C@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C@@:27]21[CH2:45][C:37]1=[N:38][CH:39]=[C:40]([C:42](O)=[O:43])[CH:41]=[C:36]1[CH2:35]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:15])([F:16])[F:17])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH:18][C:42]([C:40]2[CH:41]=[C:36]3[CH2:35][C@@:27]4([C:28]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:34][C:26]4=[O:25])[CH2:45][C:37]3=[N:38][CH:39]=2)=[O:43])[CH2:4][C@H:3]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2nnc(C3(C(F)(F)F)CC3)n21
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)c2nnc(C3(C(F)(F)F)CC3)n21
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of (5R,6S,8S)-5-methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-amine (19.0 mg, 0.056 mmol) in N,N-dimethylformamide (565 μL) were added (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (19.1 mg, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (0.77 mg, 5.7 μmol), N-methylmorpholine (14.9 μL, 0.136 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.0 mg, 0.068 mmol). The mixture was stirred 30 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (22 mg). HRMS 600.2347 (M+1). 1H NMR (400 MHz, DMSO): δ 11.13 (s, 1H); 9.39 (d, J=8.1 Hz, 1H); 8.91 (d, J=2.0 Hz, 1H); 8.15 (d, J=1.9 Hz, 1H); 8.10 (dd, J=5.3, 1.6 Hz, 1H); 7.48 (dd, J=7.3, 1.6 Hz, 1H); 7.42 (t, J=7.4 Hz, 2H); 7.38−7.29 (m, 3H); 6.94 (dd, J=7.3, 5.3 Hz, 1H); 5.49−5.40 (m, 1H); 4.70−4.62 (m, 1H); 3.72 (d, J=13.5 Hz, 1H); 3.50−3.32 (m, 4H); 2.62 (d, J=12.0 Hz, 1H); 2.36−2.28 (m, 1H); 174 (d, J=10.3 Hz, 1H); 1.64−1.52 (m, 2H); 1.27−1.20 (m, 1H); 1.18 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20].O=[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19]/[N:20]=[C:25](/[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)\[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CON)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)CCCC/C(=N\OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1)c1ccccc1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
After a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), ethyl 6-oxo-6-phenylhexanoate (452 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 15 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (590 mg, yield 58%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:38]>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:37]([O:39][C:40]2[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=2)=[O:38])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a well-stirred solution of 5-benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (12 g, 29 mmol) and pyridine (10 mL) in CH2Cl2 (100 mL) was added powdered 4-nitrophenyl chloroformate (8.69 g, 43 mmol) at 0° C. The reaction mixture was stirred for 12 h at room temperature and the solvent was evaporated from the filtrate and the residue was purified by column chromatography (SiO2, dichloromethane/hexane, 20%-50%) to give the product as a foam (14.2 g, 86%).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:36][C:22]1[N:23]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[S:25][C:21]=1[CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:37])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (6-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (6-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[CH2:14](Cl)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: ClCCc1ccccc1
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OCCc2ccccc2)c1
Reaction time: 16 h

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (300 mg, 1.7 mmol) was dissolved in DMF (8.5 ml) and treated with phenethylchloride (224 μl, 1.7 mmol). Cs2CO3 (610 mg, 1.87 mmol) was then added and the reaction mixture stirred at room temp. for 16 hours. The mixture was filtered and washed with DMF(3×10 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH2:25][C:26]([N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[O:27])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2cccc3cnccc23)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1cccc2cnccc12)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-isoquinolin-5-yl-amino]-acetic acid with diethylamine