Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:23]([OH:25])=O)[S:5][C:6]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[N:12][N:11]=[CH:10]2.CC[N:28]([CH:32]([CH3:34])[CH3:33])C(C)C.C1(N)CC1>S(Cl)(Cl)=O.C(OCC)(=O)C>[CH:32]1([NH:28][C:23]([C:4]2[S:5][C:6]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:12][N:11]=[CH:10]4)=[C:2]([CH3:1])[CH:3]=2)=[O:25])[CH2:34][CH2:33]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)sc1-c1ccc2c(N3CCOCC3)nncc2c1
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)NC2CC2)sc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
4-Methyl-5-(1-morpholinophthalazin-6-yl)thiophene-2-carboxylic acid (140 mg, 309 μmol) was suspended in thionyl chloride (3.1 mL) and the mixture was heated to 65° C. for 1 h. The reaction mixture was concentrated in vacuo and azeotropically dried with toluene, then dissolved/suspended in THF 99.9% (3.1 mL) and DIPEA (216 μl, 1238 μmol) and cyclopropylamine (71 μl, 1238 μmol) were added. The mixture was stirred at RT for 2 h, then diluted with 50 mL ethyl acetate and partitioned with sodium bicarbonate (saturated, aqueous). The organics were washed 2×50 mL with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give crude yellow product, which was purified by chromatography to afford the title compound. MS (ES+): 395(M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].I[CH2:28][CH:29]([OH:32])[CH2:30][OH:31].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC(O)CI
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A solution of 7.34 g. of 4-(8-cyclohexyloctylamino)-benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1.[C:19]1([NH:25][C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[NH:27])=[CH:12][CH:13]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1
Reactant: Nc1ccc(-n2c(N)nc3ccccc32)cc1
Reactant: N#CNc1ccccc1
Agent: Cl
Solvent: CC#N
Product: N=C(Nc1ccccc1)Nc1ccc(-n2c(N)nc3ccccc32)cc1

Procedure:
A mixture of 2-Amino-N-(4-aminophenyl)benzimidazole hydrochloride (1.58 g, 6.06 mmol), phenylcyanamide (2.79 g, 23.6 mmol) and acetonitrile (10 ml) was refluxed for 3 days. The solid product was filtered off. The product was recrystallized from acetonitrile (300 ml). Yield 1.3 g, 57%. M.p. 265-267° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([CH:20]4[CH2:22][CH2:21]4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:29]1([C:39]([N:17]2[CH2:18][CH:19]([CH:20]3[CH2:21][CH2:22]3)[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Fc1ccc(C2CCN(CC3CNCC3C3CC3)CC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C2CC2)C1
Reaction time: 1 h

Procedure:
To a solution of 0.02 g (0.067 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclopropyl)pyrrolidine and 0.12 mL of pyridine in 2 mL of CH2Cl2 at rt was added 0.19 g (1 mmol) of 1-naphthoyl chloride and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between ethyl acetate and sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (HPLC Waters Nova-Pak 8×10 RCM 25-40% MeOH in H2O 0.5%TFA) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC#N.O>C(Cl)(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[Br:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)C(Br)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a stirred solution of biphenyl-4-yl-acetic acid methyl ester (5 g., 22.1 mmol) in carbon tetrachloride (from Acros, 16772) (25 mL) was added N-bromosuccinimide (from Aldrich, 18350) (3.9 g., 22.1 mmol) and benzoyl peroxide (from Acros, 21178) (0.54 g, 2.2 mmol) and the reaction was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated in vacuo to afford Cpd. 2 as a crude yellow oil (6.24 g., 93% yield). 1HNMR (CDCl3) δH, 3.81, 3H (s, CH3), 5.41, 1H (s, Br—CH), 7.33-7.39, 2H (m, Ar—H), 7.41-7.46, 3H (m, Ar—H), 7.54-7.63, 4H (m, Ar—H); LCMS analysis (solvent MeCN/H2O/0.1% HCO2H, 5-95% gradient/H2O 2.5 min, 95% 4 min., Phenomenex C18 reverse phase, flow rate 1 mL/min.) HPLC retention time 4.39 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.Cl.[NH2:20][CH2:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:14]([NH:20][CH2:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:16])[CH:10]([CH3:11])[CH2:12][CH3:13])([CH3:2])[CH3:3]
Reactant: NCc1nc2ccccc2[nH]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a room temperature solution of 0.505 g N-(tert-butoxycarbonyl)-L-isoleucine in 10 ml of methylene chloride is added, in the following order, 0.50 g of 2-(aminomethyl)benzimidazole dihydrochloride hydrate, 1.07 g of BOP and 0.850 g of triethylamine. The reaction is stirred at room temperature for 2 hours, diluted with methylene chloride, and washed with saturated sodium chloride. The organic layer is dried, filtered, and concentrated in vacuo. Purification by chromatography (silica gel; 70% ethyl acetate/hexane) gives 0.669 g of the desired product.
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:2]#[CH:3].O.[OH-].[Na+].[I:20]I>CO.O1CCCC1>[I:20][C:3]#[C:2][CH2:1][N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: C#CCn1c2ccccc2c2ccccc21
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: IC#CCn1c2ccccc2c2ccccc21
Temperature: 4 °C
Yield: 63 %

Procedure:
Procedure: To a solution of 1.23 g (0.006 mol) of N-(2-propynyl)carbazole in 19.2 mL of methanol 4.8 mL of water and 0.48 g of NaOH were added while stirring at 4° C. Addition of 6 mL of tetrahydrofurane (THF) to the turbid suspension resulted in a homogeneous solution. Then 1.52 g of crystalline iodine was added portion-wise. After 10 min of stirring the iodine color disappeared and the product started to separate as a dense white precipitate. Over 8 hrs of stirring at room temperature the product was filtered, washed with distilled water and air dried. 1.25 g (Yield 65%) of N-(3-Iodo-2-propynyl)carbazole has been obtained as crystals having m.p. 151-152° C. When applied onto a printing paper and analyzed according to Example 1, the compound gave an intense NIR FT-Raman spectrum in some features similar, but clearly not identical, to that shown in FIG. 1(A) for copper phenylacetylide (exemplary Compound #26 of the invention).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[C:25](=[O:26])[O:24][C:23](=O)[C:12]=4[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:29][NH2:30].[C:31]([OH:34])(=O)[CH3:32]>>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:13]3[C:9]4[C:8](=[CH:7][CH:6]=[C:5]5[O:1][CH2:2][O:3][C:4]5=4)[CH:10]=[C:11]4[C:25](=[O:26])[N:29]([NH:30][C:31](=[O:34])[CH3:32])[C:23](=[O:24])[C:12]=34)=[CH:22][C:18]=2[O:19][CH2:20]1
Reactant: CC(=O)O
Reactant: O=C1OC(=O)c2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: NN
Solvent: O
Product: CC(=O)NN1C(=O)c2cc3ccc4c(c3c(-c3ccc5c(c3)OCO5)c2C1=O)OCO4
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of anhydride 1 (145 mg, 0.4 mmol) in glacial acetic acid (10 mL) was refluxed with hydrazine hydrate (0.023 mL, 0.48 mmol) for 24 h under nitrogen and then poured, after cooling, into ice water. The resulting precipitate was filtered and dried under reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (30:1 to 20:1, v/v) to give 25 (143 mg, 86%) as a yellow solid. mp 281-283° C.; 1H NMR (CDCl3) δ 8.34 (s, 1H, H4), 7.69 (d, 1H, H5, J=8.7 Hz), 7.46 (s, 1H, NHAc), 7.38 (d, 1H, H6, J=8.7 Hz), 6.84-6.87 (m, 3H, H2′+H5′+H6′), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=16.5 Hz, J=1.5 Hz), 5.98 (AB, 2H, 7,8-OCH2O—, Δδ=5.4 Hz, J=1.2 Hz), 2.17 (s, 3H, NHCOCH3); MS (EI) m/z 418 [M]+.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([N:16]=[C:17]=[S:18])(=[O:15])[O:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[Cl:9][C:6]1[C:7]2[N:8]=[C:17]([NH:16][C:11](=[O:15])[O:12][CH2:13][CH3:14])[S:18][C:2]=2[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: CCOC(=O)N=C=S
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1nc2c(Cl)nc(C)nc2s1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a mixture of 4,6-dichloro-2-methylpyrimidin-5-amine (1 g, 5.62 mmol) and O-ethyl carbonisothiocyanatidate (0.66 mL, 5.62 mmol) was added toluene (2 mL) to wet the solids completely. The mixture was placed on 100° C. oil bath for 1.5 hours, at which time, the mixture had seized to give a solid mass. The solids were cooled to ambient temperature and triturated with ether, then the resulting solids were collected by filtration to give ethyl 7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate (1.08 g, 3.96 mmol, 70.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (br. s., 1H) 4.30 (q, J=7.19 Hz, 2H) 2.69 (s, 3H) 1.30 (t, J=7.15 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:22][C:21]3[CH:24]=[C:25]([CH3:28])[C:26]([OH:27])=[C:19]([CH3:18])[CH:20]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: Cc1cc(C=O)cc(C)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=Nc2[nH]nc(Nc3cccc(Cl)c3)c2C(N)=O)cc(C)c1O

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 3,5-dimethyl-4-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.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>[CH2:12]([NH:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[CH2:13][CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CCCNC1(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCNC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 75.6 %

Procedure:
Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-propylamine (Intermediate 118, 100.0 mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (13.0 mg, 0.06 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (48.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 70° C. for Sdays. The title compound (80.0 mg, 75%) was isolated by chromatography (0-10% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH2:5][NH:4][C:3]1=[O:16]>C(O)C.[H][H].[Ni]>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]2[CH2:5][NH:4][C:3](=[O:16])[CH:2]2[CH3:1])=[CH:12][CH:11]=1
Reactant: CC1C(=O)NCC1c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC1C(=O)NCC1c1ccc(N)cc1

Procedure:
45 g. of the 3-methyl-4-p-nitrophenyl-2-pyrrolidinone prepared in Example 5 are dissolved in 3 liters of absolute ethanol and hydrogenated at 100°C. with hydrogen at a pressure of 90 kg./cm.2, in the presence of 5 g. of Raney nickel as catalyst. When the hydrogen absorption has finished, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized twice from ethanol. 30 g. of 4-p-aminophenyl-3-methyl-2-pyrrolidinone are obtained. M.P. : 190°-194°C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:6]=[CH:5]2.C([Li])CCC.[C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])#[N:27]>O1CCCC1>[OH:31][CH:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[N:6]=[CH:5]2)[C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:26]#[N:27]
Reactant: N#Cc1ccccc1C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(I)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(C(O)c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
A solution of 5-iodo-1-[tris(1-methylethyl)silyl]-1H-indazole (1.8 g, 4.6 mmol) in tetrahydrofuran (9.2 mL) was cooled to −78° C., and n-butyllithium was added (1.6M in hexanes, 3.4 mL, 5.5 mmol). After 15 min., 2-cyanobenzaldehyde (0.78 g, 6.0 mmol) in 2.0 mL tetrahydrofuran was added quickly and the solution was allowed to warm to room temperature. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution, then partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted (2×100 mL ethyl acetate). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.17 g (9%) of 2-(hydroxy{1-[tris(1-methylethyl)silyl]-1H-indazol-5-yl}methyl)benzonitrile. 1H NMR (400 MHz, CDCl3): 8.20 (s, 1H), 7.95 (m, 1H), 7.69 (s, 1H), 7.51 (m, 3H), 7.23 (m, 1H), 7.09 (m, 1H), 6.50 (s, 1H), 1.77 (m, 3H), 1.06 (m, 18H); MS (EI) for C24H31N3OSi: 250 (M-SiiPr3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:16]=[N:15]2)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.ClCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:16]=[N:15]2)[CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][C:26]([OH:25])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCC(Cn1nnnc1-c1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: OC1(c2ccccc2)CCN(CCC(Cn2nnnc2-c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.03 h
Yield: 44.9 %

Procedure:
3-(3,4-Dichlorophenyl)-4-(5-phenyltetrazol-1-yl)butyraldehyde (0.200 g) in methanol (1 mL) and dichloromethane (1 mL) was added to a solution of 4-hydroxy-4-phenylpiperidine (0.147 g) and acetic acid (0.047 mL) in methanol (1 mL). After 2 minutes, sodium cyanoborohydride (52 mg) in methanol (1 mL) was added in a single portion. After being stirred overnight, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried and evaporated. The crude product was suspended in methanol/ether and filtered to give the title compound as a white solid (0.13 g); NMR: 7.57 (m,5), 7.44 (m,2), 7.36-7.18 (m,5), 6.87 (dd,1, J=1.6, 8.2), 4.98 (dd,1, J=5.2, 14.3), 4.81 (dd,1, J=10.1, 14.2), 4.71 (s,1), 3.20 (m,1), 2.54 (m,1), 2.34-2.16 (m,3), 2.09 (m,2), 1.91 (m,1), 1.75 (m,3), 1.50 (m,2); MS: m/z=522(M+1). Analysis for C28H29Cl2N5O: Calculated: C, 64.37; H, 5.59; N, 13.40; Found: C, 64.10; H, 5.56; N, 13.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]([NH:20][C:21]4([C:24]([OH:26])=O)[CH2:23][CH2:22]4)=[O:19])[N:13]3[C@:12]([CH3:39])([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[C:11]2=[O:40])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Cl.[CH3:42][N:43]1[CH:47]=[C:46]([C:48]2[CH:49]=[N:50][C:51]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[N:52][CH:53]=2)[CH:45]=[N:44]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:42][N:43]1[CH:47]=[C:46]([C:48]2[CH:53]=[N:52][C:51]([C:54]3([NH:57][C:24]([C:21]4([NH:20][C:18]([C:17]5[N:13]6[C@:12]([CH3:39])([CH2:27][C:28]7[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:30][CH:29]=7)[C:11](=[O:40])[N:10]([C:4]7[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=7)[C:14]6=[N:15][CH:16]=5)=[O:19])[CH2:23][CH2:22]4)=[O:26])[CH2:56][CH2:55]3)=[N:50][CH:49]=2)[CH:45]=[N:44]1
Reactant: Cn1cc(-c2cnc(C3(N)CC3)nc2)cn1
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc(C3(NC(=O)C4(NC(=O)c5cnc6n5[C@](C)(Cc5ccc(OC(F)(F)F)cc5)C(=O)N6c5cc(Cl)c(F)c(Cl)c5)CC4)CC3)nc2)cn1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 1-{[(R)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (130 mg, 0.22 mmol) and 1-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-cyclopropylamine hydrochloride (75 mg, 0.26 mmol) in DMF (1 mL) was added diisopropylethylamine (0.15 mL, 0.87 mmol) and HATU (990 mg, 0.24). After 1 h, the reaction mixture was purified by reversed phase MPLC (C18, 30 g, Mobile phase: CH3CN (0.1% TFA), water (0.1% TFA), Gradient: 70% water to 10% water). The pure fractions were combined and concentrated in-vacuo to remove most of the CH3CN and then partitioned between 50 mL of CH2Cl2, 20 mL of water, and 10 mL of saturated aqueous NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to afford 146 mg of the title compound as a white foam, m/z=798.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:19]=2)C(N(OC)C)=O)[CH:5]=[CH:6][CH:7]=1.C[Li].[Cl-].[NH4+:23].C([O:27][CH2:28][CH3:29])(=O)C>C1COCC1.CCOCC>[NH2:23][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:12]=1[C:28](=[O:27])[CH3:29]
Reactant: [NH4+]
Reactant: CCOC(C)=O
Reactant: CON(C)C(=O)c1cccc(-c2cccc(Cl)c2)c1
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenyl boronic acid (5.63 g, 36 mmol), tetrakis(triphenylphosphine)palladium (0) (1.73 g, 1.5 mmol), and sodium carbonate, (7.63 g, 72 mmol) in a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and heated at 85° C. under nitrogen for 3 hours. The reaction, mixture was cooled to room temperature and treated with brine (30 mL) and ethyl acetate (100 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine and dried with MgSO4. After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to give 5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added in a dropwise fashion a solution of methyllithium in ether (1.4M, 28.6 mL, 40 mL) at −78° C. under nitrogen. After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (50 mL) at −78° C. Ethyl acetate (100 mL) was added, organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed (brine) and dried (MgSO4). After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane: ethyl acetate/2:1) to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone as a yellow solid (2 g, 47%): mp 89-90° C.; 1H-NMR (CDCl3) δ 7.89 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.25-7.40 (m, 3H), 6.73 (d, 1H, J=8.6 Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268([M+Na]+, 60%); Anal. Calc. For C14H12ClNO: C, 68.44; H, 4.92; N, 5.70. Found: C, 68.40; H, 4.89; N, 5.61.
Reaction SMILES: C1(N[N:8]=[C:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][C:11]3[CH:17]=[CH:18][CH:19]=[N:20][C:10]2=3)C=CC=CC=1.[K+].[Br-].[C:23](#N)[CH3:24].O>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:20]1[C:10]2[C:9]3[NH:8][C:24]4[C:23]([C:15]=3[CH2:14][C:13](=[O:16])[NH:12][C:11]=2[CH:17]=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:15]=4
Reactant: O=C1CCC(=NNc2ccccc2)c2ncccc2N1
Reactant: CC#N
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1Cc2c([nH]c3ccccc23)-c2ncccc2N1

Procedure:
Prepared according to general procedure B from 72.4 mg (0.27 mmol) 7,8-dihydro-5H-pyrido[3,2-b]azepine-6,9-dione 9-(phenylhydrazone) in 30 ml diphenyl ether. Recrystallization from ethanol afforded a brown solid. Yield: 17 mg (25%); m.p. >330° C.; IR (KBr): 3054 cm−1 (CH-arom.), 2974 cm−1 (CH-aliph.), 1675 cm−1 (C═O), 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=3.66 (s, 2H, azepine-CH2), 7.06-7.09 (m, 1H, arom. H), 7.18-7.22 (m, 1H, arom. H), 7.40 (dd, 1H, 8.2/4.5 Hz, arom. H), 7.47 (d, 1H, 8.2 Hz, arom. H), 7.62 (dd, 1H, 8.2/1.4 Hz, arom. H), 7.70 (d, 1H, 8.0 Hz, arom. H), 8.48 (dd, 1H, 4.5/1.4 Hz, arom. H), 10.22 (s, 1H, NH), 11.70 (s, 1H, NH); 13C-NMR (DMSO-d6, 100.6 MHz): δ (ppm)=31.9 (azepine-CH2), 111.9, 118.4, 119.1, 122.5, 122.8, 129.3, 144.3 (tert. arom. C), 108.9, 126.3, 132.0, 132.5, 137.5, 140.5 (quat. arom. C), 171.1 (C═O); C15H11N3O (249.27); purity (HPLC): 98.8% (ts=3.25 min, acetonitrile/water 35:65).