Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:3]1=2.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[NH:20]1[C:16]([C:14]2[CH:13]=[CH:12][C:4]3[O:5][C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:11]4[C:2](=[O:1])[C:3]=3[CH:15]=2)=[N:17][N:22]=[N:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2oc3ncccc3c(=O)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(-c3nnn[nH]3)ccc2oc2ncccc12
Reaction time: 20 h
Yield: 71.5 %

Procedure:
A mixture of 34 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbonitrile, 460 ml of dimethylformamide, 10.5 g of ammonium chloride and 13.1 g of sodium azide is heated with stirring at 110° C to 120° C for 20 hours. After cooling, crystals are filtered off and added to a dilute hydrochloric acid, and the mixture is stirred. The crystals are filtered off, washed with water and recrystallized from dimethylformamide to give 29 g of 7-(5-1H-tetrazolyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at above 300° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([O:18][CH2:19][CH:20](O)[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][CH2:19][CH:20]([O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC(COCc1ccccc1)COCc1ccccc1)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A suspension of 5-chloro-pyrazine-2-carboxylic acid (prepared as in Example 29, 1.00 g, 6.33 mmol) in methylene chloride (30 mL) was treated with 1,3-dibenzyloxy-2-propanol (2.06 g, 7.57 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.61 g, 6.34 mmol), and triethylamine (1.83 mL, 12.66 mmol). The mixture was stirred at 25° C. overnight. The solution was extracted with methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water, a saturated aqueous sodium chloride solution, a 1N aqueous hydrochloric acid solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/1 hexanes/ethyl acetate) afforded the 5-chloropyrazine-2-carboxylic acid 2-benzyloxy-1-benzyloxymethyl-ethyl ester (1.45 g, 55.7%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1)CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)Cc1ccc(OC)cc1
Yield: 100.5 %

Procedure:
Ethyl 2-ethyl-3-(4-methoxyphenyl)acrylate (4.58 g, 19.5 mmol), 5% palladium on carbon (500 mg) and ethyl acetate (100 mL) were mixed and hydrogenated for 8 hours at room temperature. After the catalyst was removed by filtration, the filtrate was concentrated to afford 4.63 g (100%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1>>[CH3:14][C:12]1([CH3:15])[N:13]=[C:9](/[CH:8]=[CH:1]/[C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[O:10][CH2:11]1
Reactant: O=Cc1ccco1
Reactant: CC1=NC(C)(C)CO1
Product: CC1(C)COC(/C=C/c2ccco2)=N1

Procedure:
4,4-Dimethyl-2(2-α-furylethenyl)-2-oxazoline (P-1906) was prepared by reacting furfural with 2,4,4-trimethyl-2-oxazoline. The product had a boiling point of 87° at 0.14 mm and the nmr spectrum and infra-red absorption spectrum were consistent with the proposed structure. The oral LD0 by adminstration to mice was 50 mg/kg; the LD50 was 212 and the LD100 was 300 mg/kg.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])[CH2:3][CH3:4].[OH-].[Na+].O>C(O)C>[ClH:1].[CH2:2]([N:5]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[NH:24])[NH2:25])=[CH:19][CH:18]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7])[CH2:3][CH3:4]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(CCC(=O)O)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.52 g (1.0 mMol) of 1-Methyl-2-[(4-amidinophenyl)-thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was dissolved in 15 ml ethanol, mixed with 5 ml of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then 5 ml of water were added, the alcohol was distilled off, and it was acidified with concentrated hydrochloric acid. The water was distilled off in vacuo, and the crude product was taken up in 5 ml of ethanol and filtered to remove the insoluble sodium chloride. After the solvent had been distilled off the title compound was obtained as a white solid. Yield: 0.43 g (88% of theory), Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5) C23H27N5O3S (453.57) ##EQU10##
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][C:4]=2[N:3]=1.[C:19]1([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[NH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:19]1([C:25](=[N:26][C:2]2[CH:11]=[CH:10][C:9]3[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][C:4]=3[N:3]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cl)ccc2C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nc(N=C(c3ccccc3)c3ccccc3)ccc2C1
Temperature: 110 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.09 g, 4.05 mmol), diphenyl-methanimine 26 (2.20 g, 12.14 mmol), Pd(OAc)2 (181.6 mg, 0.809 mmol), BINAP (503.8 mg, 0.809 mmol), Cs2CO3 (6.59 g, 20.23 mmol) and toluene (16 mL) were added. The reaction mixture was heated at 110° C. for 2 days. The reaction mixture was filtered and removed solvent in vacuo. The residue 158a was directly used in the next step.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:34][C:35]1[O:39][N:38]=[C:37]([N:40]2[CH2:45][CH2:44][CH:43]([CH2:46][C:47](O)=[O:48])[CH2:42][CH2:41]2)[CH:36]=1>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH:25][C:47](=[O:48])[CH2:46][CH:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[C:35]([CH3:34])[O:39][N:38]=2)[CH2:45][CH2:44]1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)no1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCC(CC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 8 %

Procedure:
The desired compound was prepared according to the procedure of Example A169, step B using 6-chloro2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and [1-(5-methylisoxazol-3-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting materials in 8% yield. LCMS for C29H31ClN7O2 (M+H)+: m/z=544.2.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(C1C=CC=CC=1C(C)C)(C)C.[Cu]>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: CC(C)c1ccccc1C(C)C
Agent: O=C([O-])[O-]
Product: Cc1ccc(-n2c3ccccc3c3ccccc32)cc1
Yield: 76.7 %

Procedure:
10.0 g (59.8 mmol) of carbazole, 17.0 g (78.0 mmol) of 4-iodotoluene, 11.0 g (79.6 mmol) of potassium carbonate and 760 mg (12.0 mmol) of copper powder were allowed to react in 200 ml of diisopropylbenzene at 210° C. for 30 hours. The mixture was cooled to 80°-90° C., and filtered on sellaite. The filtrate was concentrated, and the residue was recrystallized from isopropanol to obtain 11.8 g of 9-p-tolylcarbazole.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])[CH3:3].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:13]>>[F:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:12](=[O:13])[O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(C)(F)c1cc(N)no1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)no1
Yield: 100 %

Procedure:
Prepared from 5-(2-fluoropropan-2-yl)isoxazol-3-amine (40 mg, 0.278 mmol) and 4-chlorophenyl chloroformate (54 mg, 0.28 mmol) according to the procedure described in Example 122A Step 3, to afford 4-chlorophenyl 5-(2-fluoropropan-2-yl)isoxazol-3-ylcarbamate as a colorless solid (83 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 8.11 (brs, 1H), 7.36-7.40 (m, 2H), 7.12-7.17 (m, 2H), 6.83 (s, 1H), 1.76 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24])([O-:19])=[O:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1cccc([N+](=O)[O-])c1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3-nitrobenzoic acid
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:13])[C:8]([O:10]CC)=[O:9])[NH:4][N:3]=1.O.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([CH3:13])[C:8]([OH:10])=[O:9])[NH:4][N:3]=1
Reactant: CCOC(=O)C(C)c1cc(C)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(C)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.3 %

Procedure:
To a solution of 1.24 g (6.8 mmol) of ethyl 2-(3-methyl-1H-pyrazol-5-yl)propanoate from step B above in 20 mL of methanol and 5 mL of water was added 1.5 mL (7.5 mmol) of an aqueous 5.0 M sodium hydroxide solution. The resulting mixture was stirred at ambient temperature for 2.5 h and then evaporated in vacuo to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×75 mL) then acidified with a 2 N hydrochloric acid solution until a pH of 4 was achieved. The aqueous solution was extracted with ethyl acetate (5×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a yellow gum (0.80 g, 76%). 1H NMR (CDCl3, 500 MHz) δ 10.23 (br s, 1H), 7.26 (s, 1H), 5.97 (s, 1H), 3.87 (q, J=7.3 Hz, 1H), 2.26 (s, 3H), 1.59 (d, J=7.3 Hz, 3H). LC-MS: m/z (ES) 155 (MH)+.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:27])([CH3:26])[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CC(C)([O-])C.[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH3:26][C:8]1([CH3:27])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:11]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH2:14][CH2:13]2)[C:9]1=[O:10]
Reactant: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)C(C)(C)c3nccnc3Cl)CC2)nc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: Cc1ccc(N[C@H]2CC[C@@H](N3C(=O)C(C)(C)c4nccnc43)CC2)nc1
Temperature: 90 °C
Reaction time: 17 h
Yield: 32.8 %

Procedure:
To a glass microwave reaction vessel was added 2-(3-chloropyrazin-2-yl)-2-methyl-N-(cis-4-((5-methylpyridin-2-yl)amino)cyclohexyl)propanamide (0.1050 g, 0.271 mmol), RuPhos Precatalyst (0.012 g, 0.016 mmol, Strem Chemicals), and sodium tert-butoxide (0.052 g, 0.541 mmol, Sigma-Aldrich Chemical Company, Inc.) in dry dioxane (0.271 ml) to stir at 90° C. for 17 h. Solvent was evaporated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.0313 g, 0.089 mmol, 32.9% yield). LCMS showed product peak at 1.526 min (m+1=352.1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 6 H) 1.52 (d, J=11.93 Hz, 2 H) 1.64 (t, J=13.60 Hz, 2 H) 1.98-2.14 (m, 5 H) 2.58 (d, J=10.37 Hz, 2 H) 3.91 (br. s., 1 H) 4.16-4.30 (m, 1 H) 6.16 (br. s., 1 H) 6.58 (d, J=8.41 Hz, 1 H) 7.24 (dd, J=8.31, 2.05 Hz, 1 H) 7.81 (s, 1 H) 8.15 (d, J=3.13 Hz, 1 H) 8.16-8.21 (m, 1 H)
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[O:37]=[C:38]([N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[O:37]=[C:38]([N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(CC(=O)N5CCCC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 197.3 mg of 1-(2-oxo-2-pyrrolidin-1-ylethyl)piperazine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:20])[C:9]=1[C:10]1[S:11][C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[C:5]#[N:6].C[Si]([Br:25])(C)C>C(#N)CC>[Br:25][C:13]1[C:12]2[S:11][C:10]([C:9]3[C:8]([F:20])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[Cl:1])=[N:18][C:17]=2[CH:16]=[CH:15][N:14]=1
Reactant: N#Cc1cc(F)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: N#Cc1cc(F)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Yield: 101.7 %

Procedure:
A suspension of 3-chloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorobenzonitrile (0.077 g, 0.24 mmol) and trimethylsilyl bromide (63 μL 0.48 mmol) in propionitrile (2.4 mL) was heated under reflux for 5 hours before further trimethylsilyl bromide (30 μL, 0.24 mmol) was added. The resulting mixture was heated under reflux for a further 16 hours then partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired compound as an off-white solid (0.090 g, quant. yield). 1H NMR (300 MHz, CDCl3): δ 8.53 (d, J=5.6 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H), 7.72 (t, J=1.4 Hz, 1H), 7.52 (dd, J=8.3; 1.5 Hz, 1H). LCMS (Method D): RT=3.89 min, m/z: 368 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=3)[CH:26]=2)[CH:10]=1.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C(#N)C.C(Cl)Cl>[CH3:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:28]=3)[CH:26]=2)[CH:10]=1
Reactant: ClCCN1CCCC1
Reactant: CNc1cc(-c2cncc(-c3cccc(O)c3)c2)cc(-c2ccccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CNc1cc(-c2cncc(-c3cccc(OCCN4CCCC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
Potassium carbonate (3.0 eq, 0.686 mmol, 95 mg) is added to a suspension of 3-(6′-Methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenol (Example 2.189, step 1) (1.0 eq, 0.229 mmol, 81 mg) in dry acetonitrile (2.0 ml) under an inert atmosphere of nitrogen. 1-(2-Chloro-ethyl)-pyrrolidine (3 eq, 0.686 mmol, 92 mg) is added and the reaction is heated using microwave radiation at 150° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 453.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:8]=2)[N:3]=1.[NH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:21][C@H:22]2[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]2)[CH:11]=[CH:10]3)=[CH:15][CH:16]=1
Reactant: Fc1ccc(COc2ccc3nc(Cl)ccc3c2)cc1
Reactant: N[C@@H]1CCc2ccccc21
Product: Fc1ccc(COc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1
Temperature: 130 °C
Yield: 5.9 %

Procedure:
A stirred mixture of 2-chloro-6-(4-fluoro-benzyloxy)-quinoline (0.08 g, 0.4 mmol) and (R)-1-aminoindane (0.107 g, 1.00 mmol) was heated in a sealed tube for 20 h at 130° C. Purification by flash chromatography on silica gel (ethyl acetate in heptane, 0→80%) yielded the title compound as a dark oil (9 mg, 8%), MS 385.6 [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10]3)[CH:2]=1.C(N)CN>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(-c3cccnc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: c1cncc(-c2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
5-Pyridin-3-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (Preparation #17c, 100 mg, 0.31 mmol) and ethylenediamine (133 μL, 2.00 mmol) were dissolved in 1M tetrabutylammonium fluoride in THF (4.0 mL) and the mixture was heated at reflux for about 2 hours. The reactions was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (25 mL), washed with water (2×10 mL) and concentrated under reduced pressure. The crude product was further purified by reverse phase preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min) to yield 5-pyridin-3-yl-1H-indazole (61 mg, 64%) as an off-white solid. RP HPLC (Table 1, Method e) Rt=1.65, m/z: (MH)+ 196.
Reaction SMILES: C#C.[CH2:3]([Mg]Br)[CH3:4].[CH3:7][C:8]([CH3:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]=[O:10].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:8]([CH3:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]([OH:10])[C:3]#[CH:4]
Reactant: CC[Mg]Br
Reactant: CCCCC(C)(C)C=O
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)C(C)(C)CCCC
Reaction time: 0.75 h

Procedure:
To a solution containing 90 parts of acetylene dissolved in 600 parts by volume of tetrahydrofuran is added, over a period of about 50 minutes at -70°, 600 parts by volume of tetrahydrofuran containing 133 parts of ethyl magnesium bromide. Acetylene gas is continuously passed through the mixture during the addition period. Following that addition, the mixture is stirred at approximately -40° for about 45 minutes. To that mixture is then added, with stirring under nitrogen over a period of about 1 hour, 80 parts by volume of 2,2-dimethyl-n-hexaldehyde dissolved in 350 parts by volume of tetra=hydrofuran. Stirring at room temperature is continued for about 16 hours, at the end of which time approximately 125 parts by volume of saturated aqueous ammonium chloride is added slowly with stirring. The precipitate which forms is removed by filtration and the filtrate is partially concentrated, then diluted with ether and again filtered. The filtrate is stripped of solvent, then is distilled under reduced pressure to afford 4,4-dimethyl-1-octyn-3-ol, boiling at about 55°-65° at a pressure of about 3 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9]C)=[O:8].O[Li].O>CO.O>[Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]ccc1Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Methyl 3-chloro-1H-pyrrole-2-carboxylate (18.86 mmol, 1.0 equiv.) was dissolved in MeOH—H2O (2:1, 120 ml); at 0° C., LiOH.H2O (75.4 mmol, 4 equiv.) was added and the mixture was stirred for 16 h at 25° C. The methanol was concentrated under reduced pressure, and the aqueous residue was diluted with water (60 ml) and extracted with ethyl acetate (2×50 ml). The aqueous phase was adjusted to pH 3-4 with 1 M HCl, and the resulting solid was filtered out. Yield: 90%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CCN2
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2C(C)=O
Temperature: 60 °C
Yield: 91.8 %

Procedure:
To a solution 5-(methyloxy)-2,3-dihydro-1H-indole (8.9 g, 59.8 mmol, 1.0 eq) in acetic acid (120 mL) was added dropwise acetic anhydride (6.1 g, 59.8 mmol, 1.0 eq). The mixture was heated at 60° C. for 15 minutes. The reaction was quenched by pouring into water (100 mL). After cooling, a grey precipitate was formed, the precipitate was filtered by a Buchner funnel and rinsed with water to afford 1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indole (10.5 g, 91% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.13 (d, J=6.3 Hz, 1 H), 6.74-6.71 (m, 2 H), 4.05 (t, 2 H), 3.78 (s, 3 H), 3.17 (t, 2H), 2.21 (s, 3 H).