Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:17]1([C:29]2[C:30]([O:35][CH2:36][CH3:37])=[N:31][CH:32]=[CH:33][CH:34]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[NH:19][C:18]1=[O:28].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH2:36]([O:35][C:30]1[C:29]([C:17]2([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[NH:19][C:18]2=[O:28])=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:37]
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(C#N)cc21
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncccc1C1(Nc2ccc(CN3CCN(C)CC3)cc2)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
4-(4-Methyl-piperazin-1-ylmethyl)phenylamine (425 mg, 2.07 mmol) was added to a solution of 3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (500 mg, 1.59 mmol) in dichloromethane (50 ml) and DIPEA (0.27 ml, 159 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then an aqueous NaHCO3 solution was added. The aqueous reaction mixture was extracted with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification by chromatography (silica gel, 0-20% methanol in dichloromethane) afforded 791 mg of the title compound (99% yield).
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(NCC(F)(F)F)ncn1
Temperature: 60 °C
Reaction time: 9 h
Yield: 24.4 %

Procedure:
To 2 ml of dimethylsulfoxide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 220 mg of potassium carbonate, and 495 mg of 2,2,2-trifluoroethylamine, followed by stirring at a bath temperature of 60° C. for 9 hours. Then, 495 mg of 2,2,2-trifluoroethylamine was further added, and the mixture was stirred at 80° C. for 8 hours. Then, 495 mg of 2,2,2-trifluoroethylamine and 2 ml of dimethylsulfoxide were further added, and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 60 mg of 4-(2-butynyloxy)-6-(2,2,2-trifluoroethylamino)pyrimidine (the present compound (114)).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)cc(F)c3)c(=O)n12
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solutions of 7-(1-azidoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.15 g, 0.43 mmol) (1 st peak from chiral separation) in tetrahydrofuran (2 mL) and water (0.5 mL) were added 1.00 M of trimethylphosphine in tetrahydrofuran (0.52 mL, 0.52 mmol) at room temperature and the mixtures were stirred at room temperature for 1 hour. To the mixture was added EtOAc and the mixture was extracted with aqueous 1 N HCl solution (three times). The combined extracts were neutralized with solid Na2CO3 and extracted with dichloromethane (two times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the desired product (134 mg, 96.6%). LCMS calculated for C15H14F2N3OS (M+H)+: m/z=322.1. Found: 322.0.
Reaction SMILES: C(N(CC)CC)C.[F:8][S:9]([F:20])([F:19])([F:18])([F:17])[C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26](=[O:27])[NH:14][C:13]1[CH:12]=[CH:11][C:10]([S:9]([F:17])([F:18])([F:19])([F:20])[F:8])=[CH:16][CH:15]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (13.9 g, 137 mmol) was added to a stirred solution of 4-(pentafluoro-λ6-sulfanyl)aniline (Commercially available, for example from Apollo Scientific, Stockport, UK, 10.0 g, 45.6 mmol) in DCM (100 mL) at 0° C. and the mixture was stirred for 15 mins. 2-Chloro-2-oxoethyl acetate (7.47 g, 54.7 mmol) was added at 0° C., and the temperature was raised to room temperature with stirring continued for 4 hr. The reaction mixture was diluted with DCM and washed with ice water, saturated aq NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by recrystallisation from ether (500 mL) to give the title compound (8.64 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH3:42])[C:32]2[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][CH:33]=2)(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15].C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH3:42])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([OH:40])=[O:39])=[CH:36][CH:37]=2)(=[O:29])=[O:30])(=[O:20])=[O:21])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15]
Reactant: COC(=O)c1ccc(N(C)S(=O)(=O)c2ccccc2S(=O)(=O)Oc2cc(C)cc(OCCCONC(=N)N)c2)cc1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)c2ccc(C(=O)O)cc2)c1
Yield: 84 %

Procedure:
The title compound was prepared in 84% yield from 3-[5-methyl-3-(2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride, as prepared in step b of Example 50, in a manner analogous to Example 27. 1H-NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=7.4 Hz, 1H), 7.97 (t, J=7.6 Hz, 1H), 7.90 (m, 4H), 7.61 (br s, 4H), 7.40 (d, J=7.7 Hz, 2H), 6.74 (s, 1H), 6.45 (s, 2H), 3.98 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 3.46 (s, 3H), 2.19 (s, 3H), 2.01 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H28N4O9S2: 593.1 (M+H), 615.1 (M+Na), 631.1 (M+K). Found: 593.1, 615.0, 630.9.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([NH:18][C@H:19]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[CH2:20][C:21](OC)=[O:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].CO.Cl>ClCCl>[F:31][C:27]1[CH:26]=[C:25]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:20][CH:21]=[O:22])[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (1 M in dichloromethane, 39 ml, 39 mmol) was cooled to −78° C. and added dropwise to a solution of methyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propanoate (WO 0039125) (5.4 g, 18.2 mmol) in dichloromethane (100 ml) at −78° C. The reaction was stirred for 30 minutes at −78° C., then methanol (50 ml, pre-cooled to −78° C.) was added. The reaction was stirred for 30 minutes, then 2 N hydrochloric acid (250 ml) added. The bi-phasic mixture was allowed to warm up to room temperature, the layers were separated, and the organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a clear, colourless oil, 4.8 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18](Br)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[SH:35]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18]([S:35][C:31]3[NH:30][CH:34]=[CH:33][N:32]=3)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2]
Reactant: Sc1ncc[nH]1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Sc3ncc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 24 %

Procedure:
(3-Cyclopentanecarbonyl-4-{3-[5-(1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-ureido}-phenyl)acetic acid ethyl ester (120 mg, 24%) was prepared from {4-[3-(5-bromo-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-acetic acid ethyl ester (480 mg, 1 mmol) and 1H-imidazole-2-thiol (200 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: O[CH2:2][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][S:5][CH3:6].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:20]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:25])[N:19]1[CH2:2][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][S:5][CH3:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CSCC(CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [1-hydroxy-3-(methylsulfanyl)propan-2-yl]carbamate (14.0 g, 63.3 mmol) in THF (200 mL) was added phthalimide (11.2 g, 76.0 mmol) and triphenylphosphine (25.3 g, 94.9 mmol) under a nitrogen atmosphere. Diethylazodicarboxylate was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfanyl)propan-2-yl]carbamate. MS ESI calc'd. for C17H22N2O4SNa [M+Na]+ 373. found 373. 1H NMR (400 MHz, CD3OD) δ 7.85-7.77 (m, 4H), 4.16-4.05 (m, 1H), 3.92-3.68 (m, 2H), 2.69-2.15 (m, 2H), 2.15 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)c1ccccc1
Solvent: O
Product: C[C@H](O)c1ccccc1
Reaction time: 192 h
Yield: 42 %

Procedure:
Continuing, using these immobilized beads as catalyst, 400 ml of distilled water equal to 20 times the weight of tartary buckwheat curd were added as reaction solvent. After making the temperature of the distilled water 35° C. using a constant-temperature shaking culturing vessel, 201 mg of ±-1-phenylethanol were added as substrate after which the conditions of the culturing vessel were set to 55 rpm and substrate conversion was performed for 8 days. (S)-1-phenylethanol was obtained at a conversion rate of 50%, optical purity of 95% e.e. and yield of 42% by going through the fourth and fifth steps under similar conditions as used with green pea protein. The yield of the formed acetophenone was 51% (102 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH3:16])[CH2:4][CH2:3]1.CN1CC=C(C)CC1CCC1C=CC=CC=1.[OH-].[Na+]>O>[CH3:16][C:5]12[CH2:6][CH:7]([N:2]([CH3:1])[CH2:3][CH2:4]1)[CH2:8][CH2:9][C:10]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1=CC(CCc2ccccc2)N(C)CC1
Agent: CC1=CCN(C)C(CCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC2(C)CC1CCc1ccccc12
Temperature: 150 °C
Reaction time: 48 h

Procedure:
A mixture of 1,4-dimethyl-6-phenethyl-1,2,3,6-tetrahydro-pyridine and 1,4-dimethyl-2-phenethyl-1,2,3,6-tetrahydro-pyridine (ca. 3:1, 1.0 g) dissolved in polyphosphoric acid (5 mL) is stirred at 150° C. for 2 d. After cooling to ca. 80° C., water (30 mL) is added and the mixture is stirred vigorously for another 5 min. Then, the mixture is cooled in an ice bath, more water is added, and the mixture is basified using 40% NaOH in water. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure to yield the title compound.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[CH3:29][C:30]1([CH3:42])[CH2:34][C:33]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=2[O:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:36]2[CH:37]=[CH:38][C:32]3[O:31][C:30]([CH3:29])([CH3:42])[CH2:34][C:33]=3[CH:35]=2)=[C:3]([CH3:28])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(C)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 82.1 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.76 g) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.50 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.72 g, 82%) as a colorless solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:18][CH2:19][CH3:20])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]=1[CH3:7].C([Sn](CCCC)(CCCC)[C:26]1[N:30]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[N:29]=[CH:28][CH:27]=1)CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:19]([O:18][C:4]1[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]([CH3:7])=[C:2]([C:26]2[N:30]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)[N:3]=1)[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: CCOc1nc(Br)c(C)n1-c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOc1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n1-c1cccc(C(F)(F)F)c1
Temperature: 94 °C

Procedure:
A solution of 4-bromo-2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole (3.14 g, 9 mmol) and 4-(5-tributylstannyl-pyrazol-1-yl)-benzonitrile (see WO2014009425A1, which is incorporated herein by reference in its entierty) (6.19 g, 13.5 mmol) in 1,4-dioxane (45 mL) was degassed by bubbling argon through the solution for 5 minutes. Tetrakis(triphenylphosphine)palladium(O) (0.52 g, 0.45 mmol) was added and after a further period of degassing the mixture was heated at 94° C. under an argon atmosphere during 17 h. The mixture was cooled to RT and filtered through a 50 g flash SCX 2 cartridge. The cartridge was eluted with DCM, 10% methanol in DCM then a 1:1 mixture of 2M ammonia in methanol and DCM. Concentration of the appropriate fractions in vacuo afforded the crude product. This was triturated with cyclohexane and dried in vacuo to afford the title compound (3.01 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:25][CH2:26][CH2:27][OH:28]>CN(C=O)C.C(OCC)(=O)C>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[C:8]([O:10][CH2:25][CH2:26][CH2:27][OH:28])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: OCCCCl
Reactant: COC(OC)c1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(OC)c1cc(OCCCO)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 22 h
Yield: 94.2 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde dimethyl acetal (5.33 g) is dissolved in dry DMF (50 ml), and thereto are added potassium carbonate (6.91 g), sodium iodide (7.5 g) and 3-chloropropanol (4.73 g), and the mixture is stirred at 70° C. for 22 hours. To the mixture is added ethyl acetate, and the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give 5-(3'-hydroxypropyloxy)-2-nitrobenzaldehyde dimethyl acetal (6.39 g) as a pale yellow oil.
Reaction SMILES: C(N(C[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10]1)CCC)CC.[NH3:18]>ClCCl.CO>[N:18]1([CH2:9][CH:14]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10]2)[CH2:10][CH2:9][CH2:14][CH2:13][CH2:12]1
Reactant: CCCN(CCC)CC1CCCN(CC#N)C1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: N#CCN1CCC(CN2CCCCC2)C1

Procedure:
2-[3-[(dipropylamino)methyl]-piperidin-1-yl]acetonitrile in a yield of 76% of theory, RF 0.545 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 89/10/1 v/v);
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9].F[C:50](F)(F)C1C=C(C(N)C)C=CC=1>>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH:6]([C:5]4[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:4]=4)[CH3:50])[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CC(NC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)O)c2)c1)c1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared using the procedure used to prepare 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoic acid 1.1, using 1-(3-(trifluoromethyl)phenyl)ethanamine in place of 3-(trifluoromethyl)benzylamine. 1H-NMR (300 MHz, CD3OD, ppm): δ 9.044-9.062 (d, J=5.4 Hz, 1H), 8.786-8.816 (d, J=9.0 Hz, 1H), 8.378 (s, 1H), 8.125-8.133 (d, J=2.4 Hz, 1H), 8.003 (s, 1H), 7.875-7.905 (m, 2H), 7.707-7.754 (m, 3H), 7.499-7.623 (m, 4H), 5.324-5.393 (m, 1H), 3.913 (s, 2H), 3.678-3.714 (m, 4H), 2.709-2.754 (m, 2H), 2.574-2.618 (m, 2H), 2.043-2.060 (m, 4H), 1.831-1.846 (m, 2H), 1.641-1.664 (d, j=6.9 Hz, 3H). MS (ES, m/z): 692 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[OH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]2[CH2:30][CH2:31][CH:27]([OH:26])[CH2:28]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: OC1CCNC1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)N2CCC(O)C2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and, 70 mg (0.784 mmol) of 3-hydroxypyrrolidine, 13 mg (11.1% of theory) of 2-[2-ethoxy-5-(3-hydroxy-pyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2]triazin-4-one are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([OH:21])[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O.C(OCC)(=O)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([OH:21])[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C2(O)CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 1.10 g of 8-[4-(tert-butyl)phenyl]-1,4-dioxaspiro[4.5]decane-8-ol. Then, 5.00 ml of 6 mol/L hydrochloric acid and 5.00 ml of water were added at an ice-cooled temperature and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the resulting crystal was collected by filtration to obtain 0.67 g of 4-[4-(tert-butyl)phenyl]-4-hydroxy-1-cyclohexanone as a colorless crystalline product.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:31]([O:33][CH:34]=[CH2:35])=[O:32]>ClCCCl>[C:24]1([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:31]([O:33][CH:34]=[CH2:35])=[O:32])[CH2:9]3)[C:14](=[O:17])[CH:13]=[CH:12]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=COC(=O)Cl
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)C=CC(c3ccccc3)(c3ccccc3)C2C1

Procedure:
A mixture of 2-benzyl-7,7-diphenyl-2,3,3a,4,7,7a-hexahydro-4-1H-isoindolone (3.4 g) and vinyl chloroformate (0.92 cc) in 1,2-dichloroethane (80 cc) is refluxed for 1 hour; the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from ethyl ether (20 cc). 7,7-Diphenyl-2-vinyloxycarbonyl-2,3,3a,4,7,7a-hexahydro-4-1H-isoindolone (2.6 g) melting at 162° C. is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:5][CH:4]([CH2:3][CH:2]1[NH:1][C:11](=[O:13])[O:9][C:7]1=[O:8])[CH3:6]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)CC1NC(=O)OC1=O
Temperature: 45 °C

Procedure:
L-Leucine (15.00 g, 0.1144 mol) was heated to 100° C. under vacuum overnight, suspended in THF (150 ml) and stirred at 45° C. in a 3-neck flask with a reflux condenser fitted, under N2 pressure. Triphosgene (13.574 g, 0.4 eq) was added via a solid addition tube. After ca 80 min, the reaction had gone clear and the mixture was washed with dry diethyl ether (1 L) through the filter agent Celite (5 cm deep) in a sinter funnel (diameter 8 cm porosity 3) to a RB flask.