Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:16]3[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(4-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as an orange solid (0.080 g). The filtrate was concentrated in vacuo, and purification of the residue on a isolute silica column using 1 to 5% methanol in ethyl acetate as eluant gave an additional 0.055 g of the product (total yield: 68%); 1H-NMR (500 MHz, DMSO-d6) 2.53 (br s, 4H, piperazine N(CH2)2), 3.08 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2), 6.97 (s, 2H, NH2), 7.34 (d, J=5.88 Hz, 2H), and 8.51 (d, J=4.48 Hz, 2H) (pyrid-4-yl protons), 8.16 (s, 1H, 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.00 min—393, 395 [(M+H)+, Br isotopic pattern].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC=C)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:22]C)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[CH2:34](N(CC)CC)C.C(O)=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:34])([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(CC)c2cccc(C(F)(F)F)c2)c1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
2.00 g (4.12 mmol) of 2-[3-(4-chlorophenyl)-4-allyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 371 are dissolved in 20 ml degassed dioxan and treated under argon with 97 mg of tetrakis(triphenylphosphine)-palladium(0) (0.084 mmol), 1.46 ml (10.44 mmol) of triethylamine and 0.32 ml (8.35 mmol) of formic acid and stirred for two hours at 85° C. The suspension is then allowed to cool to room temperature and the precipitated crystals are filtered off at the pump and washed with isopropanol. The mother liquor is concentrated in vacuo and treated with isopropanol, during which further crystals deposit, which are likewise suction-filtered and washed with isopropanol. Together 1.56 g (85% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(OCC)C>ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][CH:18]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: OB(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Reaction time: 8 h

Procedure:
2-Methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (II-1) (200 mg, 1.01 mmol) was dissolved in 10 mL dichloromethane. Powdered molecular sieves (3 Å, 200 mg), 4-fluorobenzene boronic acid (284 mg, 2.02 mmol) and [Cu(OH)TMEDA]2Cl2 (47 mg, 0.10 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 min and stirring was continued at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→85:15 gradient) and a mixture of 2 regioisomers was isolated. The desired compound was obtained by recrystallization from diethylether as a white solid (151 mg, 51%), mp=151° C., MS: m/e=292.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2].[I-].[K+].[CH2:28]([CH:31]=[CH:32][CH2:33][NH2:34])[CH2:29][CH3:30]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:34][CH2:33][CH2:32][CH2:31][CH2:28][CH:29]=[CH2:30])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: CCCC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 39, 8-nitro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and propylallylamine in tetrahydrofuran are reacted to give 8-nitro-1-[(allylpropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 46 8-Fluoro-1-[(allylethylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:22]=[C:23]1[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][N:24]1[CH2:40][C:41](O)=[O:42].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:41](=[O:42])[CH2:40][N:24]3[CH2:25][CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:23]3=[O:22])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(bis(4-fluorophenyl)methyl)piperazine (0.29 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42-7.47 (m, 4H), 7.21-7.33 (m, 10H), 7.11-7.17 (m, 4H), 4.41 (s, 1H), 4.14-4.15 (br s, 2H), 3.37-3.47 (m, 4H), 3.35 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.21-2.26 (m, 4H); MS (DCI+) m/z 566 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:3]=1
Reactant: O=C(c1ccccc1)c1cn(-c2cccc(Br)c2)cn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1ccccc1)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Temperature: 70 °C

Procedure:
A solution of 7 (250 mg, 0.76 mmol), phenylboronic acid (102 mg, 0.84 mmol) and Na2CO3 (244 mg, 2.3 mmol) in DME/H2O 4:1 (10 mL) was thoroughly purged with argon, after which Pd(PPh3)2Cl2 (36 mg; 0.05 mmol) was added and the mixture was heated to 70° C. for 21 h. The solvents were removed in vacuo and the residue was purified by column chromatography (1 to 5% methanol in CH2Cl2 to give 100 mg (41%) pure 8. HRMS (ESI+): m/z=324.3814 [M+H]
Reaction SMILES: N[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([Br:13])=[C:6]([F:14])[C:3]=1[C:4]#[N:5].N(OC(C)(C)C)=O.O>O1CCCC1>[Br:13][C:7]1[C:6]([F:14])=[C:3]([CH:2]=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c(N)c([N+](=O)[O-])cc(Br)c1F
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])cc(Br)c1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a cooled (0° C.) solution of 2-amino-5-bromo-6-fluoro-3-nitro-benzonitrile (8.0 g, 30.8 mmol) in tetrahydrofuran (40 mL) was added tert-butyl nitrite (4.6 mL, 37 mmol) dropwise and stirred for 16 h at 50° C. The reaction mixture was treated with water and extracted with ethyl acetate. The organic fraction was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (2% to 10% ethyl acetate:hexanes) afforded 4.0 g (53%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.72 (dd, J=3.0, 2.7 Hz, 1H), 8.51 (dd, J=3.0, 2.7 Hz, 1H).
Reaction SMILES: [C:1](Cl)([CH3:4])([CH3:3])[CH3:2].[Mg].[Sn:7]([Cl:11])(Cl)(Cl)[Cl:8].[Cl-].[Mg+2].[Cl-]>CCCCCCC.O1CCCC1>[C:1]([Sn:7]([Cl:11])([Cl:8])[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: CC(C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Sn](Cl)(Cl)C(C)(C)C

Procedure:
The Grignard reagent from t-butyl chloride (92.5 g., 1 mole), magnesium (24.3 g., 1 mole) and tetrahydrofuran (11.) was added dropwise to a solution of tin(iv) chloride (104 g., 0.4 mole) in heptane (11.). A vigorous reaction started at once and magnesium chloride precipitated. After completion of the addition, the mixture was refluxed for 4 hrs. Cooling and work-up gave a yellow oil. This was distilled to give the desired product as a clear oil which solidified readily (70.0 g., 58%), m.p. 42°-43° (lit., 142°); b.p. 66°/3 mm.; n.m.4. 81.45(s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[CH:11][N:12]=[C:13](Cl)[C:8]2=[N:7][C:6]=1[CH2:15][CH3:16])=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1B(O)O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[CH:11][N:12]=[C:13]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][C:22]=3[Cl:24])[C:8]2=[N:7][C:6]=1[CH2:15][CH3:16])=[O:4]
Reactant: CCc1nc2c(Cl)nccn2c1C(=O)OC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1C(=O)OC
Yield: 77.4 %

Procedure:
8-Chloro-2-ethylimidazo[1,2-a]pyrazine-3-carboxylic methyl ester (0.92 g, 3.8 mmol) synthesized in Reference Example 1 was dissolved in a mixed solvent of toluene (32 mL) and methanol (8 mL), then 2,4-dichlorobenzeneboronic acid (1.49 g, 7.8 mmol) and tetrakistriphenylphosphine palladium complex (230 mg, 0.2 mmol) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was allowed to cool, and purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (1.03 g) as a pale yellow crystals.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].[CH3:12][CH:13]([CH3:18])[CH:14]=[CH:15][O:16]C>P(=O)(O)(O)O>[CH:15]([CH:14]([CH:13]([CH3:18])[CH3:12])[CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:16]
Reactant: C=C(C)C1CCC(C)(O)C1=C
Reactant: COC=CC(C)C
Agent: O=P(O)(O)O
Product: C=C(C)C1CCC(C)=C1CC(C=O)C(C)C
Yield: 45 %

Procedure:
According to the procedure described in Example 7, by the reaction of 30.4 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol with 50 g of methyl (3-methyl-1-butenyl) ether in the presence of 7 drops of 85% phosphoric acid there was obtained 2-(2-formyl-3-methylbutyl)-3-isopropenyl-1-methyl-cyclopent-1-ene in 45% yield; boiling point 0.005 = 55°-56° C; nD20 = 1.4808; IRfilm : νmax = 3280, 2725, 1725, 1642, 1460/40, 1390/70 and 890 cm-1. The compound has a cedar-like, woody, remotely floral fragrance.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)[CH:2]=[CH2:3]>C1COCC1.CO.[C].[Pd]>[NH:22]1[CH:23]=[C:19]([C:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=3)[CH:10]=2)([OH:18])[CH:15]([CH3:17])[CH3:16])[N:20]=[CH:21]1
Reactant: C=CCc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 162.7 %

Procedure:
1-(6-Allylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.40 g) was dissolved in THF-methanol (1:2) (15 ml). To the solution was added 10% palladium carbon (140 mg), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The catalyst was filtered and washed with THF. The filtrate was concentrated. The residue was chromatographed on silica gel (eluent, hexane:THF=1:1) and crystallized from isopropyl ether-hexane to give the titled compound (1.28 g) as a colorless powder.
Reaction SMILES: CCN=C=NCCCN(C)C.CN(C=O)C.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32](O)=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:41])[CH:37]([CH3:39])[CH3:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32]([NH:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:41])[CH:37]([CH3:38])[CH3:39])=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: O=C(O)c1cc2ccccc2n1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
DMAP (122 mg, 1.0 mmol) and EDAC (249 mg, 1.3 mmol) were added as solids to a DMF solution of 1-phenylindole-2-carboxylic acid (237 mg, 1.0 mmol in 2 ml, DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (306 mg, 1.0 mmol in 2 mL of methylene chloride) was added to the reaction mixture and the mixture was stirred for 1 hour under a nitrogen atmosphere at 0° C. and 4 hours at room temperature. The yellow reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give a colorless film (0.827 g). The film was subjected to flash chromatography on silica gel with ethyl acetate/hexanes (1:2) to yield the title product as a white foam (400 mg, 78%). TLC: (ethyl acetate/hexanes 1: 1): Rf=0.27.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH3:26])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO200687543, 1.18 g, 6.15 mmol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.33 g, 6.15 mmol) in dichloromethane (170 mL) were added HOBT (941 mg, 6.15 mmol) and N-methyl morpholine (2.02 mL, 18.45 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (2.11 g, 11.07 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by flash column chromatography (silica, 35% ethylacetate in pet ether) afforded ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.9 g (49%) as solid.
Reaction SMILES: C(C1C=C2C(=CC=1)C(=O)OC2)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:19](=[O:20])[O:18][CH2:17]2.C([Cu])#N>>[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:19](=[O:20])[O:18][CH2:17]2.[NH2:13][C:14]1[CH:15]=[C:16]2[C:17](=[O:18])[NH:2][C:19](=[O:20])[C:21]2=[CH:22][CH:23]=1
Reactant: N#Cc1ccc2c(c1)COC2=O
Agent: N#C[Cu]
Agent: Nc1ccc2c(c1)COC2=O
Product: Nc1ccc2c(c1)C(=O)NC2=O

Procedure:
A method for the preparation of 5-cyanophthalide has previously been described in Bull. Soc. Sci. Bretagne, 1951, 26, 35 and in Levy and Stephen, J. Chem. Soc., 1931, 867. By this method 5-aminophthalide is converted to the corresponding 5-cyanophthalide by diazotation followed by reaction with CuCN. 5-Aminophthalide was obtained from 4-aminophthalimide by a two step reduction procedure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:11])[N:6]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[N:7]=2)[CH:3]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2cc(Br)ccc2nn1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole (2.0 g) in N,N-dimethylformamide (20 ml) were added (2-bromoethoxy)(tert-butyl)dimethylsilane (2.5 g) and 60% sodium hydride (682 mg) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (492 mg).
Reaction SMILES: NCC([O-])=O.[Na+].C(OC(=O)C)(=O)C.C([N:17]1[CH:21]=[C:20]2[CH2:22][CH:23]([NH:26]C(=O)C)[CH2:24][CH2:25][C:19]2=[CH:18]1)(=O)C>>[CH2:24]1[CH:23]([NH2:26])[CH2:22][C:20]2[C:19](=[CH:18][NH:17][CH:21]=2)[CH2:25]1
Reactant: CC(=O)NC1CCc2cn(C(C)=O)cc2C1
Agent: NCC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: NC1CCc2c[nH]cc2C1

Procedure:
According to Reaction Scheme I, 4-acetamido cyclohexanone, prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970) is reacted with the dimethylacetal of dimethylformamide to yield 2-dimethylaminomethylene-4-acetamidocyclohexanone (III). Reacting this compound with sodium glycinate followed by a ring closure reaction in the presence of acetic anhydride yields, when R3 is methyl, dl-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (IV). Treatment of this latter compound with base gives dl-5-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (V). This latter compound can be preferentially alkylated on the amino group at C-5 using a reductive alkylation procedure; i.e., reaction with an aldehyde (formaldehyde, acetaldehyde, acrolein, or propionaldehyde) in the presence of a strong organometallic reducing agent such as sodium cyanoborohydride. The dialkylated compound, for instance, dl-5-di(n-propyl)amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole (VI) can also be alkylated on the pyrrole ring nitrogen under basic conditions using an alkyl halide R2X (methyl iodide, allyl chloride, ethyl bromide, or the like) to yield a dl-2-(C1 -C3 alkyl or allyl)-5 -disubstituted-amino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole of Formula VII.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]([C@H:23]2[CH2:27][CH2:26][C@@:25]3([CH2:31][CH2:30][N:29]([CH3:32])[C:28]3=[O:33])[NH:24]2)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]([C@H:23]3[CH2:27][CH2:26][C@@:25]4([CH2:31][CH2:30][N:29]([CH3:32])[C:28]4=[O:33])[NH:24]3)[CH:16]=2)[CH:9]=1)[CH3:2]
Reactant: CCc1cnc([C@H]2CC[C@@]3(CCN(C)C3=O)N2)cc1Br
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(F)c(-c2cc([C@H]3CC[C@@]4(CCN(C)C4=O)N3)ncc2CC)c1
Temperature: 140 °C
Yield: 73.3 %

Procedure:
To a microwave vial containing a solution of (5-ethoxy-2-fluoro-phenyl)boronic acid (54.39 mg, 0.3000 mmol) in MeCN (1 mL) and water (0.2000 mL) was added (2R,5S)-2-(4-bromo-5-ethyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 122) (80 mg, 0.2400 mmol), sodium carbonate (50.12 mg, 0.4700 mmol) and bis(triphenylphosphine)palladium (II) dichloride (8.2 mg, 0.0100 mmol). The microwave vial was sealed and heated at 140° C. for 15 minutes. The reaction was concentrated in vacuo and loaded onto a silica column (10 g, Biotage SNAP cartridge). The silica column was then eluted with a gradient of (80:20:2 EtOAc:MeOH:0.88M NH3):EtOAc from 0% to 100%. Fractions containing desired product were combined and concentrated in vacuo to give (2R,5S)-2-[4-(5-ethoxy-2-fluoro-phenyl)-5-ethyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (69.9 mg, 0.1759 mmol, 74.4% yield) as a colourless oil;