Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[C:22]=[O:23]>CO>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:29][CH:28]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (27 mg, 0.17 mmol) and diisopropylethylamine (88 uL, 0.51 mmol) in MeOH (2 mL) was added 1-isocyanato-4-phenoxybenzene (71 mg, 0.34 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities were dissolved in the ether/EtOAc and discarded and the remaining material was taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (10 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.30 (m, 4H), 7.07 (t, 1H, J=7.2 Hz), 6.95-6.92 (m, 4H), 4.73-4.71 (m, 1H), 3.80-3.54 (m, 2H), 3.26 (s, 9H), 2.81-2.68 (m, 2H); MS ESI 372.2 [M+H]+, calcd for [C20H25N3O4+H]+ 372.43.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])(C)(C)C.Cl>O1CCOCC1>[ClH:20].[Cl:20][C:11]1[C:10]([F:21])=[C:9]([CH:14]=[C:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH:12]=1)[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2nn[nH]n2)cc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(-c2nn[nH]n2)cc(Cl)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of [3-chloro-2-fluoro-5-(2H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester (1.06 g, 3.23 mmol) in dioxane (20 mL) was added a 4M HCl solution in dioxane (8.09 mL, 32.3 mmol). The reaction mixture was stirred at RT for 72 h and then freeze-dried overnight to afford the title compound as a white solid. MS (LC/MS): 228.0 [M+H]+; tR (HPLC conditions c): 2.68 min.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>ClCCl.O>[C:22]([O:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[C:5]([C:6]#[N:7])=[CH:8][C:9]=1[CH3:10])=[O:28])(=[O:24])[CH3:23]
Reactant: Cc1cc(C#N)c(C(F)(F)F)cc1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 4-amino-5-methyl-2-(trifluoromethyl)benzonitrile (Intermediate 60, 300 mg, 1.50 mmol) and triethylamine (0.230 mL, 1.65 mmol) in dichloromethane (8 mL) was added 2-chloro-2-oxoethyl acetate (0.161 mL, 1.50 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Reaction mixture was diluted with DCM (100 ml) and water (50 ml) and aqueous was extracted with DCM (100 ml). Organics were combined, passed through a phase separator and concentrated to afford 452 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[N:7]=[C:6](Cl)[CH:5]=1.C(N(CC)C(C)C)(C)C.[CH2:27]([NH2:30])[C:28]#[CH:29]>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH:30][CH2:27][C:28]#[CH:29])[N:7]=[C:8]([S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:9]=1
Reactant: C#CCN
Reactant: COC(=O)c1cc(Cl)nc(S(=O)(=O)C(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNc1cc(C(=O)OC)cc(S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Yield: 19.1 %

Procedure:
Add THF (10 mL), 2-chloro-6-iso-propanesulfonyl-isonicotinic acid methyl ester (0.50 g, 1.80 mmol), N,N-diisopropylethylamine (0.470 mL, 2.70 mmol), and propargylamine (0.740 mL, 10.8 mmol) to a sealed vessel flushed with nitrogen. Heat and stir the reaction at 80° C. overnight. Cool to room temperature, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title product (0.102 g, 19%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[C:5]([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C.O>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:11]=[C:10]([OH:12])[C:9]3[C:4](=[C:5]([CH:16]4[O:20][CH2:19][CH2:18][O:17]4)[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=3)[N:3]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc(C2OCCO2)c2nc(Cl)nc(O)c2c1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C2OCCO2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A solution of 2-chloro-8-(1,3-dioxolan-2-yl)-4-hydroxy-6-nitroquinazoline (2.9 g), 3,4-dichloroaniline (3.2 g) and N,N-diisopropylethylamine (2.52 mL) in N,N-dimethylacetamide (145 mL) was heated to 140° C. for 3.3 hours. The mixture was then cooled to room temperature and diluted with water (2 L). The aqueous solution was separated into two equal portions, and each portion was extracted with ethyl acetate (7×100 mL). The combined ethyl acetate extracts were washed with 2N hydrochloric acid until all of the excess 3,4-dichloroaniline was removed, dried over Na2SO4, filtered and evaporated to afford the title compound as a brown solid (2.6 g). 1H NMR (300 MHz, DMSO-d6): 8.67 (d, J=2.7 Hz, 1H), 8.48 (d, J=2.7 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.42 (dd, J=2.7, 8.7 Hz, 1H), 6.23 (s, 1H), 4.09 (m, 4H). HPLC Method A: 7.76 min.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)OC(=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.CC(O)=O.[Pd]>[NH2:9][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)C(c2ccccc2)(c2ccccc2)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of (S)-4-benzyl-5,5-diphenyl-2-oxazolidinone (7) (940 mg, 2.85 mmol) in MeOH/AcOH and a 10% Pd (121 mg, 1.14 mmol) on activated carbon was shaken for 43 h under 4–5 atm pressure of hydrogen at room temperature. The catalyst was filtered off over Hyflo Super Cell and organic solvents were evaporated under reduced pressure. The resulting residue was treated with HCl, stirred for 2 h at room temperature, made basic with NaOH pellets, and saturated with K2CO3 and NaCl. Organics were then extracted into dichloromethane (4×50 ml), dried over MgSO4/K2CO3 and concentrated under reduced pressure to obtain a crude product. Purification over silica gel, eluting with a 3:7 and 4:6 mixture of AcOEt and petroleum ether, gave the title compound (8) (584 mg, 71%) as a light-brown solid. m.p. 71–72° C. [α]D25=−8.03° (c, 0.1046 in CHCl3). δH 1.21 (2H, broad s, NH2), 2.29 (1H, dd, 3J=9.6 Hz, 2J=13.5 Hz, CH2—Ph), 2.79 (1H, dd, 3J=2.1 Hz, 2J=13.2 Hz, CH2—Ph), 3.71 (1H, d, 3J=9.9 Hz, CH—Ph2), 3.81 (1H, ddd, 3J=2.7, 9.9 and 12.6 Hz, CH—NH2), 7.06–7.33 (15H, m, Ar—H), δC 41.9 (CH2—Ph), 55.7 and 59.7 (CH—Ph2 and CH—NH2), 126.3, 126.5, 126.6, 128.1, 128.2, 128.4, 128.7, 128.8 and 129.1 (o-, m- and p-Ar), 139.7, 142.6 and 143.1 (α-Ar). ir 3387 (NH2). m/e (CI—NH3) 288 (MH+, 100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:25])[CH:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:8].[CH3:26][N+:27]([O-:29])=[O:28].Cl>O.CS(C)=O>[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1([CH2:26][N+:27]([O-:29])=[O:28])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:8]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 3000-mL 4-necked round-bottom flask was placed potassium carbonate (93.2 g, 662 mmol, 0.50 equiv) and DMSO (2000 mL). The resulting solution was heated to 80° C. This was followed by the addition of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (368 g, 1.30 mol, 1.00 equiv, 95%) and CH3NO2 (417 g, 6.70 mol, 5.00 equiv, 98%) slowly. The resulting solution was stirred for 120 min at 90° C. After being cooled to room temperature, the reaction mixture was adjusted to ph 5 with HCl (0.5 mol/L) and diluted with 2000 mL of water. The resulting solution was extracted with 3×1500 mL of ether. The organic layers were combined, washed with 1×2000 mL of water and 1×2000 mL of saturated brine, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:15-1:10) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: COC(=O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1ccc(Sc2ccc(N)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionate (2.97 g, 9.33 mmol) in methanol (50 mL) were added sodium borohydride (0.590 g, 15.6 mmol) and 10% palladium-carbon (1.80 g), and the resulting solution was stirred for 24 hours at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through Celite, and to the resulting filtrate was added concentrated hydrochloric acid (1.5 mL), and concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate, and the ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 2.49 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[C:4]2[N:23]=[CH:24][CH:25]=[CH:26][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34]>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>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[N:7][C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=3)=[C:3]3[CH:26]=[CH:25][CH:24]=[N:23][C:4]=23)[C@H:9]([CH3:22])[CH2:10]1)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
Reactant: N#Cc1ccc(B(O)O)cc1
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: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C#N)cc2)c2cccnc12
Yield: 21.6 %

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (360 mg, 979 mmol), 2 M sodium carbonate (979 μl, 196 mmol), 4-cyanophenylboronic acid (216 mg, 1.47 mmol), and tetrakis(triphenylphosphine)palladium (57 mg, 49 μmol) afforded (R)-4-(8-(4-benzoyl-2-methylpiperazin-1-yl)pyrido[2,3-d]pyridazin-5-yl)benzonitrile 85 (138 mg, 32% yield) after chromatographic purification. MS 434.2 (calc'd) 435.1 (M+H, found).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][N:17]=1>>[CH3:12][N:11]([CH3:13])[C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=3[C:16]([C:15]([F:14])([F:26])[F:25])=[N:17]2)=[CH:3][CH:4]=1
Reactant: CN(C)C(=O)Cc1ccc(Br)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: CN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 2-(4-bromophenyl)-N,N-dimethylacetamide and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:15][CH:16]=[C:10]2[CH2:9]1)C1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>[OH-].[OH-].[Pd+2].CO>[CH:16]1[N:15]=[C:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=12
Reactant: CC(C)(C)OC(=O)NCc1ncc2n1CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ncc2n1CCNC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 109 %

Procedure:
To a flask was added tert-butyl (7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)methylcarbamate (0.500 g, 1.46 mmol, prepared using O from Preparation #S.1 with Boc2O), MeOH (20 mL) and Pd(OH)2 on carbon (20 wt %, 0.255 g, 0.363 mmol). The mixture was evacuated and purged with N2 three times and a H2 balloon was fitted to the flask. The flask was purged with H2 three times and stirred for about 6 h at rt. The mixture was filtered and the solvent was removed under reduced pressure to give tert-butyl (5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)methylcarbamate (0.40 g, 109%): LC/MS (Table 2, Method e) Rt=1.58 min; MS m/z: 253 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: COc1ccc(OC)c(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 76.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,5-di-methoxyaniline (133 mg, 0.87 mmol) to provide 200 (114 mg, 76% yield) as a white solid. LC-MS (M+H=348, obsd.=348).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:27])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(C)CBr
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)Cc3ccc(O)cc3)cc2)C1
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)Cc3ccc(OCC(C)C)cc3)cc2)C1

Procedure:
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamide was reacted with isobutyl bromide by method H. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
Reaction SMILES: [CH:1](=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[O:18])[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>>[OH:10][CH:1]1[CH2:2][C@@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]2[C:11](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[O:17]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C/C=C/c1ccccc1
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Product: O=C1CCCC2=C1[C@H](c1ccccc1)CC(O)O2

Procedure:
This example describes a representative Michael addition reaction between (E)-cinnamaldehyde and 1,3-cyclohexanedione, catalyzed by the hydrochloride salt of (1), to provide (4S)-2-hydroxy-4-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[CH:6]([OH:35])[C@@H:7]([NH:10][C:11](=[O:34])[C@@H:12]([NH:21][C@@H:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:23]([F:26])([F:25])[F:24])[CH2:13][S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:8][CH3:9])[CH2:3][CH2:2]1>C(#N)C.ClCCl>[CH:1]1([NH:4][C:5](=[O:36])[C:6](=[O:35])[C@@H:7]([NH:10][C:11](=[O:34])[C@@H:12]([NH:21][C@@H:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:23]([F:25])([F:24])[F:26])[CH2:13][S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:8][CH3:9])[CH2:3][CH2:2]1
Reactant: CC[C@H](NC(=O)[C@H](CS(=O)(=O)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1
Solvent: ClCCl
Solvent: CC#N
Product: CC[C@H](NC(=O)[C@H](CS(=O)(=O)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(=O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a stirred suspension of (3S)—N-cyclopropyl-3-((R)-3-((cyclopropylmethyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)-2-hydroxypentanamide [63.2 g; 118 mmol] in a mixture of acetonitrile (1150 mL) and dichloromethane (1150 mL) previously cooled in a cold water bath, was added DMP (69.86 g; 164.7 mmol; 140 mol %) in portions. The resulting reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was concentrated in vacuo to distill about 1 L of solvent and the remaining solution was added to a mixture of 1M aqueous sodium thiosulfate (800 mL) and saturated aqueous sodium bicarbonate (800 mL). Ethyl acetate (1.6 L) was added and the biphasic mixture stirred for 1.5 h. The layers were separated and the organic phase was washed with water, a mixture of water and a solution of sodium chloride in water and finally a solution of sodium chloride in water. The organic phase was dried (MgSO4) and concentrated to a wet solid which was suspended in hexane. The resulting slurry was stirred overnight, filtered and the solid was washed with hexane. Drying provided 53.6 g (85%) of the title compound. Recrystallization of this material alone with 4 g of crude (S)—N-cyclopropyl-3-((R)-3-((cyclopropylmethyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)-2-oxopentanamide from another lot (57.6 g total) using hot IPA (1700 mL) gave 52 g of a white solid after washing with cold IPA and hexane, followed by drying over P2O5 in a vacuum oven at 40° C. LC-MS, positive ion mode: m/z=536 [M+H]+ (100%); 19F-NMR (CDCl3) δ, ppm: −74.54 (s); −110.09 (s).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[N:9][C:10]([C:14]4[C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])[N:15]=4)=[N:11][CH:12]=3)[N:7](CC3C=CC(OC)=CC=3OC)[C:6]2=[O:42])[CH2:3][CH2:2]1.C([SiH](CC)CC)C.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[N:9][C:10]([C:14]4[C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])[N:15]=4)=[N:11][CH:12]=3)[NH:7][C:6]2=[O:42])[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=O)n(CC3CC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CC1CC1
Yield: 53.6 %

Procedure:
482 mg (0.70 mmol) of the compound from example 84A were dissolved in 21 ml of trifluoroacetic acid, 817 mg (7.02 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was admixed with water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum, and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 156 mg of the title compound were obtained (53% of theory).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:37])([F:36])[C@:30]([OH:35])([CH3:34])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[C@@:30]([OH:35])([CH3:34])[C:29]([F:37])([F:36])[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: C[C@](O)(C(=O)O)C(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)[C@](C)(O)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and (S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=419.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:28])[NH:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[F:27])=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[NH:19][C:18]([C@@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c(F)cccc1F)[C@H]1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (50 mg, 129 μmol, Eq: 1.00) in CH2Cl2 (6 mL) was added TFA (2 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to provide (S)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[OH-].[K+]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1OCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCOc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 70 °C
Yield: 90.7 %

Procedure:
A mixture of methyl 2-(2-t-butoxycarbonylaminoethoxy)-4-methylsulfonylbenzoate (8.6 g, 23 mmol), EtOH (200 mL), and KOH (6.5 g, 115 mmol) in water (200 mL) was heated to 70° C. for 4 hours. The EtOH was removed in vacuo and the residue was diluted with CH2Cl2. The mixture was acidified with satd citric acid and partitioned. The organic layer was dried (Na2SO4) and concentrated to give the desired product as a solid (7.5 g, 91%).