Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:11][C:12]3([O:24][N:25]=2)[CH2:16][CH2:15][N:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:13]3)[CH:5]=[CH:6][CH:7]=1.Cl[C:27]1C=C(C#CC2CC3(CCN(C(OC(C)(C)C)=O)C3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:11][C:12]3([CH2:27][CH2:13][N:14]([C:17]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[O:18])[CH2:15][CH2:16]3)[O:24][N:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: O=C(N1CCCC1)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Product: O=C(N1CCCC1)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 106 but replacing Compound 22d for Compound 27c. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 7:3 to 3:7) giving 52 mg of the title compound giving pale yellow solid. Yield: 72.6%.
Reaction SMILES: I[CH:2]1[CH2:10][CH:9]2[CH2:11][C:5]3([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]([CH2:12][CH:3]1[CH2:4]3)[CH2:8]2.CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC>C1(C)C=CC=CC=1>[C:5]12([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][CH:3]([CH2:2][CH2:10]3)[CH2:4]1)[CH2:6]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(C1)C(I)C3)C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC12CC3CCC(CC(C3)C1)C2
Temperature: 90 °C
Yield: 73 %

Procedure:
The mixture of iodide 5A (0.18 mmol), AIBN (0.054 mmol), and Bu3SnH (0.54 mmol) was diluted with toluene (10 mL) and the reaction mixture was heated at 90° C. for 2 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (10/90 EtOAc/Hexane) to provide the reduction product 6A in 73% yield. Data: LC/MS (ESR) m/z 266 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][C:14]2[CH:25]=[CH:24][C:17]([CH2:18]OS(C)(=O)=O)=[CH:16][CH:15]=2)[C:4](=[O:26])[NH:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[N:27]1([CH2:18][C:17]2[CH:24]=[CH:25][C:14]([NH:13][CH:12]=[C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[O:1])[NH:3][C:4]3=[O:26])=[CH:15][CH:16]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OCc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.8 %

Procedure:
To a suspension of crude methanesulfonic acid 4-[(1,3-dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-benzyl ester (72 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) is added pyrrolidine (21 μL, 0.25 mmol). The reaction mixture is shaken at ambient temperature for 16 hours. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (3.0 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[C:16]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:30]=2)[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1csc(COc2ccc(-c3cccc(-c4ccccc4)c3)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 71 mg, 0.2 mmol) in dioxane (3.5 mL) was added to a reaction tube containing biphenyl-3-boronic acid (available from Lancaster Synthesis Ltd., Morecambe, UK; 119 mg, 0.6 mmol). A solution of potassium carbonate (74 mg, 0.5 mmol) in water (0.4 mL) was added and the mixture was degassed. A solution of bis(tricyclohexylphosphine)-palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) in dioxane (0.5 mL) was added and the tube was heated in a microwave oven at 170 degrees for 25 min. Concentrated hydrochloric acid (0.1 mL) was added and the mixture was passed through a silica gel column (1 g of silica), and washed with dimethylacetamide (2×1 mL). The filtrate was evaporated to dryness and the resulting gum was triturated twice with 50% aqueous methanol to give 2-([1,1′;3′,1″]terphenyl-4-yloxymethyl) -thiazole-4-carboxylic acid. Mass spectrum MH+=388
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>CO.CN(C=O)C>[CH3:15][N:16]([CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Nitrophenoxy)-2,3-epoxypropane (Reference Example 1-B, 4.3 g) was dissolved in methanol (30 ml) and DMF (10 ml). Dimethylamine (2M solution in methanol, 17 ml) was added and the mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in saturated sodium bicarbonate solution and ethyl acetate. The ethyl acetate layer was separated and washed twice with saturated brine, dried over anhydrous sodium sulphate, filtered and evaporated to yield an oil that slowly crystallised under high vacuum (4.79 g, 89.9%). NMR: (CDCl3, 300 MHz) 2.33 (s, 6H), 2.98 (m, 1H), 2.54 (m, 1H), 4.00 (m,3 H), 7.00 (d, 2H), 8.20 (d, 2H); M.S.: (ES+) 241 (MH+).
Reaction SMILES: C(OC(=O)[C@H](CCCCNC(OCC1C=CC=CC=1)=O)N)C1C=CC=CC=1.C(OC(=O)[C@H](C)N)C1C=CC=CC=1.C([O:48][C:49](=[O:77])[C@H:50]([CH2:62][CH2:63][CH2:64][CH2:65][NH:66]C(OCC1C=CC=CC=1)=O)[NH:51][C:52](=[O:61])[CH:53]([CH3:60])[CH2:54][CH2:55][C:56]([O:58]C)=[O:57])C1C=CC=CC=1.COC(CCC(C)C(N[C@H](C(O)=O)CCCCN)=O)=O.N[C@H](C(O)=O)CCCCN>>[C:56]([CH2:55][CH2:54][CH:53]([CH3:60])[C:52]([NH:51][C@H:50]([C:49]([OH:77])=[O:48])[CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])=[O:61])([OH:58])=[O:57]
Reactant: COC(=O)CCC(C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: COC(=O)CCC(C)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: C[C@H](N)C(=O)OCc1ccccc1
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O

Procedure:
By substituting Nε -benzyloxycarbonyl-L-lysine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23 and then treating the product by the procedures of Examples 24 and 26, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-Nε -benzyloxycarbonyl-L-lysine benzyl ester, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-L-lysine and Nα -(4-carboxy)-2-methylbutanoyl)-L-lysine are obtained.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:6]=1.[C:17]([C:21]1[CH:22]=[C:23]([NH2:26])[NH:24][N:25]=1)([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O.C1(C)C=CC=CC=1>[C:17]([C:21]1[CH:22]=[C:23]([NH2:26])[N:24]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][O:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:6]=2)[N:25]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: Ic1cnn(CCCOC2CCCCO2)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Temperature: 140 °C
Yield: 73.6 %

Procedure:
To a mixture of intermediate 113a (1.50 g, 4.46 mmol), 5-tert-butyl-2H-pyrazol-3-ylamine (620 mg, 4.46 mmol), copper (I) iodide (42 mg, 0.22 mmol) and K2CO3 (1.29 g, 9.37 mmol) was added a solution of toluene (4.6 mL), previously degassed by using a stream of argon. (R,R)-(−)-N,N′-Dimethyl-1,2-cyclohexanediamine (141 μL, 0.89 mmol) was then added and the reaction mixture was heated at 140° C. for 2.5 h under microwave irradiation. The crude reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to give the title compound (1.14 g, 73%). LCMS (Method 4): Rt 2.34 min, m/z 348 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15]1([C:20](O)=O)[CH2:19][CH2:18][CH2:17][CH:16]=1>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:20]([C:15]4[CH2:19][CH2:18][CH2:17][CH:16]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=C(O)C1=CCCC1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Product: CC1(C)C(=O)Nc2cc3[nH]c(C4=CCCC4)nc3cc21

Procedure:
Analogously to Example 11, a mixture of 0.48 g. 5,6-diamino-3,3-dimethylindolin-2-one and 0.31 g. (1-cyclopenten-1-yl)-carboxylic acid is well stirred up with 4.5 g. warm polyphosphoric acid and then stirred for 30 minutes in a bath with a temperature of 200° C. After cooling, the reaction mixture is triturated with ice water, adjusted to pH 7-8 with concentrated aqueous ammonia solution and insoluble material is filtered off with suction, washed with water and dried, 0.51 g. of crude product thereby being obtained. This is repeatedly triturated with 6 ml. amounts of methanol, 0.25 g. of substance thereby remaining undissolved. This product is triturated three times with 6 ml. amounts of a mixture of methylene chloride/methanol (1:1 v/v), 0.14 g. of the desired title compound thereby being obtained which, per mole, still contains 2/3 mole methanol and 1 mole water; m.p. 233°-235° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:20][CH3:21])=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([N:20]([CH3:21])[CH2:27][CH2:26][CH2:25][F:24])=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FCCCBr
Reactant: CNC(=O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCF)C(=O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.4 %

Procedure:
To a solution of 1-(3-iodophenyl)-N-methyl-3-isoquinolinecarboxamide (22 mg, 0.06 mmol) in DMF (4.6 mL) was added 60% NaH (16 mg, 0.39 mmol) in one portion. The mixture was stirred under Ar at room temperature for 15 min. Then, 3-fluoropropyl bromide (29 μl, 0.39 mmol) was added. After stirring at room temperature for 20 h, the mixture was quenched by adding H2O (5 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane, 0.035% Et3N), thereby affording a semisolid (4.4 mg, 37%). 1H NMR (CDCl3) d 2.04-2.24 (m, 2 H, CH2), 3.16, 3.18 (two s, total 3 H, N-methyl), 3.60-3.75 (m, 2 H, N--CH2), 4.25-4.70 (qt, J=67.8, 47.1, 5.7 Hz, 2 H, CH2F), 7.20-7.30 (m, 1 H, aromatic), 7.55-7.65 (m, 2 H, aromatic), 7.73 (t, J=7.2 Hz, 1 H, aromatic), 7.83 (d, J=7.8 Hz, 1 H, aromatic), 7.94 (d, J=8.4 Hz, 1 H, aromatic), 7.98-8.09 (m, 2 H, aromatic), 8.12 (s, 1 H, aromatic). HRMS calcd. for C20H18FIN2O: 448.0448. Found: 448.0461
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[C:6]3([CH3:21])[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1.[CH3:22][NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:25].C([O-])(O)=O.[Na+].O.C(#N)C>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].CC(O)=O.O1CCOCC1>[CH:13]1([CH2:12][N:8]2[C:7](=[O:16])[C:6]3([CH3:21])[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]3[N:3]=[C:2]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:24]([NH:23][CH3:22])=[O:25])=[CH:32][CH:31]=4)[N:11]=[CH:10][C:9]2=3)[CH2:15][CH2:14]1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3CC2CC2)cc1
Yield: 44.9 %

Procedure:
To a microwave vial equipped with a magnetic stirrer was added 2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (88 mg, 0.285 mmol), 1,4-dioxane (2 ml), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (118 mg, 0.428 mmol), NaHCO3 (saturated, 0.491 mL), and PdCl2(dppf) (209 mg, 0.285 mmol). The reaction was irradiated in the microwave at 100° C. for 40 min. The reaction solution was then poured into water, extracted with ethyl acetate three times and the combined organic layers were washed with water and then brine, then dried with Na2SO4, filtered, and the filtrate concentrated in-vacuo to give a brown residue. The aqueous layer was acidified with AcOH (pH about 5) and concentrated in-vacuo to give a grey residue. The combined residues were purified via preparative LC/MS (45-50% gradient of 10 mmol NH4HCO3 in 20/80(v/v) water/acetonitrile in 10 mmol NH4HCO3 in water, Phenomenex Gemini 5 μm C18, 75×30 mm column to give the title compound (54 mg, 0.128 mmol, 44.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.25-0.57 (m, 4H) 1.18 (m, 1H) 1.35 (s, 3H) 2.62-2.71 (m, 3H) 3.17-3.26 (m, 1H) 3.54-3.65 (m, 1H) 3.68 (d, J=11.62 Hz, 1H) 3.81 (dd, J=14.53, 6.95 Hz, 1H) 3.89-4.02 (m, 2H) 4.07 (dd, J=11.62, 3.54 Hz, 1H) 4.20 (dd, J=13.77, 2.40 Hz, 1H) 6.07 (d, J=4.80 Hz, 1H) 7.49 (d, J=8.84 Hz, 2H) 8.19 (d, J=8.84 Hz, 2 H) 8.36 (s, 1H) 8.72 (s, 1H). MS [M+H] found 423.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.96 min; [M+H]+=411.11.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][O:19][C:20](=[O:30])[C:21]([OH:29])([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22](O)=[O:23].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH3:18][O:19][C:20](=[O:30])[C:21]([OH:29])([C:22](=[O:23])[NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: COC(=O)C(O)(CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C(O)(CC(C)C)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of 350 mg (1.56 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 327 mg (1.72 mmol) (R/S)-2-hydroxy-2-isobutyl-malonic acid monomethyl ester in 30 ml tetrahydrofuran were cooled to 0° C. and 232 mg (1.72 mmol) 1-hydroxy-benzotriazole hydrate, 584 μl (3.43 mmol) diisopropylethylamine and 329 mg (192 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Extraction with water/ethylacetate and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50) yielded 470 mg (76%) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid methyl ester as a colorless foam, MS (m/e): 397.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[C:18]([C:21]1[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=1)[CH:17]=[CH:16][CH:15]=2>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]2[N:12]=[CH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:17]=[CH:16][CH:15]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: Cn1cc(-c2cccc3cnc(Cl)cc23)cn1
Product: COc1ccc(Nc2cc3c(-c4cnn(C)c4)cccc3cn2)cc1

Procedure:
The title compound was prepared according to Method 3 (Example 27) using 4-methoxyaniline and 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7).
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18].[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>C1COCC1>[CH3:18][O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[B:19]([OH:24])[OH:20]
Reactant: COc1ccc(C(F)(F)F)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M in hexanes, 456 μL, 0.729 mmol) was added dropwise to a stirred solution of 2-iodo-1-methoxy-4-(trifluoromethyl)benzene (Step A, 200 mg, 0.662 mmol) in THF (1.5 mL) at −78° C. under an atmosphere of nitrogen. The reaction stirred at −78° C. for 30 min prior to the addition of triisopropyl borate (458 μL, 1.986 mmol). The reaction stirred an additional 2 h at −78° C. and was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2 and the organic phase was washed with NaHCO3 (15 mL) and brine (15 mL), dried (Na2SO4), filtered, conc. in vacuo to afford [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid which was carried on without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[O:11]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:12]2[CH2:13][CH2:14][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[O:11]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc([C@H]2CC[C@H](c3ccc([N+](=O)[O-])cc3)O2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc([C@H]2CC[C@H](c3ccc(N)cc3)O2)cc1
Reaction time: 2 h

Procedure:
A mixture of 8 g of Compound 1 and 1 g of 5% Pd/C in 100 ml of EtOH is hydrogenated at 20 psi for 2 hours. The desired product is obtained after removal of solvent.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.[H-].[Na+].Cl[C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([CH:26]=[CH:27][N:28]=2)[N:25]=1.Cl>O1CCCC1>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([CH:26]=[CH:27][N:28]=2)[N:25]=1)[CH3:16]
Reactant: Cc1cc2nccn2nc1Cl
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(COc1nn2ccnc2cc1C)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 1.38 g of 3-(N,N-dimethylaminomethyl-ene)aminosulfonyl -2,2-diethyl-1-propanol in 30 ml of tetrahydrofuran, 0.23 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. To the reaction mixture, 0.74 g of 6-chloro-7-methylimidazo [1,2-b]pyridazine was added, followed by refluxing under heating conditions for 1 hour. After cooling, the reaction mixture was neutralizedwith 1 N hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran(1:1). After the extract was washed with water and dried over MgSO4, the solvent was distilled off under reduced pressure. To the residue was added 14 ml of 6 N hydrochloric acid, followed by stirring at 110° C. for 30 minutes. After cooling, the mixture was concentrated under reduced pressure, and the residue adjusted to a pH of 7 by addition of aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. After saline washing, the extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue subjected to column chromatography using 100 g of silica gel, eluted with chloroform-methanol (5:1), and crystallized from a mixed solvent of methanol and ethyl acetate, to yield 1.19 g of the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])C.[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12](=[O:11])[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)c1ccccc1OC
Reactant: CC#N
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)CC#N
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 2-methoxy-benzoic acid ethyl ester in 5 niL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered. The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(2-methoxy-phenyl)-3-oxo-propionitrile in the amount of 2.4954 gms.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][NH:4][C:3]1=[O:10].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:44][NH2:45].C(N1CCOCC1)C>CN(C)C=O>[Cl:33][C:34]1[C:39]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:44][NH:45][C:7]([CH:6]1[CH2:5][NH:4][C:3](=[O:10])[N:2]1[CH3:1])=[O:9]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CN1C(=O)NCC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CN1C(=O)NCC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 22 °C
Reaction time: 20 h
Yield: 49.6 %

Procedure:
Crude 3-methyl-2-oxo-4-imidazolidinecarboxylic acid (˜0.63 mmol, prepared as described below) was dissolved in dimethylformamide (3 ml) and treated with 1-hydroxybenzotriazole (0.094 g, 0.69 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.132 g, 0.69 mmol), [(2-chloro-3-trifluoromethylphenyl)methyl]amine (0.145 g, 0.69 mmol) and N-ethylmorpholine (0.169 ml, 1.32 mmol). The mixture was stirred at 22° C. for 20 hours then reduced in vacuo to give a residue which was purified by mass-directed automated HPLC to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-4-imidazolidinecarboxamide as a white solid (0.105 g). LC/MS [M+H]+=336, retention time=2.18 minutes.