Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:5]=12.Br[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=2[O:14][CH:13]=1>>[F:21][C:20]1[C:15]2[O:14][CH:13]=[C:12]([C:6]3([OH:10])[CH2:7][CH2:8][CH2:9][N:4]4[CH:3]=[N:2][CH:1]=[C:5]34)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCCn2cncc21
Reactant: Fc1cccc2c(Br)coc12
Product: OC1(c2coc3c(F)cccc23)CCCn2cncc21

Procedure:
starting from 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and 3-bromo-7-fluorobenzofuran [1288851-92-3].
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1c(-c2ccccc2)nc2ccccc2c1=O

Procedure:
3-Amino-2-phenyl-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.15 (m, 3H), 1.33-1.44 (m, 6H), 1.53-1.57 (m, 3H), 1.72-1.77 (m, 3H), 1.79-1.92 (m, 2H), 7.43-7.50 (m, 3H), 7.58-7.64 (m, 3H), 7.73-7.76 (m, 1H), 7.88-7.64 (m, 1H), 8.18-8.21 (m, 1H), 10.96 (s, 1H) ppm; MS (DCI/NH3) m/z 414 (M+H)+; Elemental Analysis: Calculated for C26H27N3O2.1.15H2O: C, 71.92; H, 6.80; N, 9.68. Found: C, 71.93; H, 6.79; N, 9.77.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](OB(O)O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[N:23]=[C:24]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([N:35]1[CH2:34][CH2:33][N:32]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[C:22]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:12][CH:13]=3)[N:23]=2)[CH2:37][CH2:36]1)[CH3:39]
Reactant: OB(O)Oc1ccc(CCOCc2ccccc2)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 72.3 %

Procedure:
4-(2-Benzyloxyethyl)phenylboric acid (0.40 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.65 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.09 g) in toluene (50 ml) and a 10% aqueous solution of sodium carbonate (30 ml) in nitrogen atmosphere for 1 hr. To the mixture was additionally added 4-(2-benzyloxyethyl)phenylboric acid (0.40 g), and the mixture was heated under reflux for 1.5 hr. 4-(2-Benzyloxyethyl)phenylboric acid (0.40 g) was again added, and the mixture was heated under reflux overnight. The organic layer was separated, and it was extracted with 2N hydrochloric acid twice. The resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system, and then ethyl acetate/acetone system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-benzyloxyethyl)phenyl]isoquinoline (0.48 g) as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C@@H:15]([CH3:16])[CH2:14][O:13][CH2:12][C@H:11]2[CH3:17])=[O:9])=[CH:4][CH:3]=1.Br[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=[C:23]([Br:25])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[C@@H:15]([CH3:16])[CH2:14][O:13][CH2:12][C@H:11]3[CH3:17])=[O:9])=[CH:6][N:7]=2)[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 320a (160 mg, 1.0 eq., 0.68 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (273 mg, 1.5 eq., 1.02 mmol), Pd2(dba)3 (64 mg, 0.1 eq., 0.070 mmol), Xantphos (79 mg, 0.2 eq., 0.14 mmol), Cs2CO3 (444 mg, 2.0 eq., 1.36 mmol), and dioxane (20 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 320b (190 mg, 66%) as a yellow solid. MS-ESI: [M+H]+ 420.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Si:14]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:27][CH3:28])=[O:24])[CH2:10]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=CC(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of 3-((2S,4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-pyrrolidin-2-yl)acrylic acid (40 g, 0.107 mol) in dry DMF (250 ml) was added iodoethane (17.3 ml, 0.23 mol), followed by K2CO3 (29 g, 0.22 mol). After stirring at RT for 4 h, K2CO3 was filtered off and solvent removed under vacuum. The residue was taken in dichloromethane, washed with brine and dried. The solvent was removed under vacuum to give tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate (35 g) as pale yellow liquid. Yield: 82%
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]4[CH:22]=[C:23]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:25][CH:26]=4)[C:14]3=[O:36])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][CH2:27][C:23]1[CH:22]=[C:21]([CH2:20][NH:19][C:15]2[C:14](=[O:36])[N:13]([C:11]3[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=3[CH3:37])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:18]=[CH:17][N:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NCc2cccc(CNC(=O)OC(C)(C)C)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NCc2cccc(CN)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A mixture of [[3-[[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]methyl]phenyl]methyl]-carbamic acid, 1,1-dimethylethyl ester (Example 51,90 mg), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (22 mg).
Reaction SMILES: [S:1]1[C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]3=[C:3]([C:14]([OH:16])=O)[CH2:2]1.[ClH:17].C(OC([NH:28][CH2:29][CH2:30][NH2:31])=O)C1C=CC=CC=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[ClH:17].[NH2:28][CH2:29][CH2:30][NH:31][C:14]([C:3]1[CH2:2][S:1][C:5]23[CH:13]=[CH:12][CH:11]=[CH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]=13)=[O:16]
Reactant: O=C(O)C1=C2C=CN=C3C=CC=CC32SC1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCCNC(=O)C1=C2C=CN=C3C=CC=CC32SC1
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In 10 ml of dimethylformamide (DMF) were suspended 487 mg of benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid synthesized in Example 17 and 508 mg of benzyloxycarbonylethylenediamine hydrochloride ##STR58## and after adding thereto 307 μl of triethylamine, the mixture was cooled to 0° C. Then, 660 mg of diphenylphosphorylazide (DPPA) and 336 μl of triethylamine were added thereto and the mixture was stirred for one hour under ice-cooling and stirred overnight at room temperature. The reaction mixture was diluted with 200 ml of ethyl acetate, washed with an aqueous 5% citric acid solution, an aqueous 5% sodium hydrogencarbonate solution, and then a saturated aqueous sodium chloride solution, and then dried by sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure, the residue was dissolved in 10 ml of acetic acid and after adding thereto 5 ml of an acetic acid solution of 25% hydrogen bromide, the mixture was stirred for 2 hours at 50° C. The reaction mixture was diluted with 200 ml of water and washed twice with ether. After adjusting the pH thereof to 11 with sodium hydroxide, the reaction mixture was extracted thrice with chloroform and the extract was dried by sodium sulfate. Chloroform was distilled off under reduced pressure and the residue was diluted with 100 ml of ethyl acetate. Then, 2 ml of a mixture of 1N hydrochloric acid in ethyl acetate was added dropwise to the residue and crystals thus deposited were collected by filtration to provide 230 mg (yield of 37%) of N-(2-aminoethyl)-benzo[b]thieno[2,3-c]pyridine-3-carboamide.hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12](O)[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C.S([Cl:29])(C)(=O)=O>C(Cl)Cl>[Cl:29][CH:12]([C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(O)c1cc(OC)c(OC)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cl)c1cc(OC)c(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To 7A (280 mg, 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0 mmol) followed by mesyl chloride (0.12 mL, 1.5 mmol). After stirring at rt overnight, the reaction was filtered, concentrated and purified via silica gel chromatography (0-30% ethyl acetate/hexanes) to provide 7B (268 mg, 89%).
Reaction SMILES: N[C:2]1[C:3]([Cl:23])=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([S:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:7]=1.N([O-])=O.[Na+].[F:28][P-](F)(F)(F)(F)F.[H+]>Cl>[Cl:23][C:3]1[C:2]([F:28])=[CH:7][C:6]([S:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: CN(C)C(=O)c1ccccc1Sc1cc(N)c(Cl)cc1[N+](=O)[O-]
Reactant: F[P-](F)(F)(F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Product: CN(C)C(=O)c1ccccc1Sc1cc(F)c(Cl)cc1[N+](=O)[O-]
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
To a solution of 2-(5-amino-4-chloro-2-nitro-phenylthio)-N,N-dimethyl-benzamide (18) (1 g, 2.84 mmol) in 6 N HCl (10 mL), a solution of sodium nitrite (0.3 g, 4.35 mmol) in wter (0.5 mL) was added at −5° C. (−0° C.). To this mixture, 48% hexafluorophosphoric acid (1.5 mL) was added at 0° C. and the mixture was stirred for 10 min. The precipitate was collected by filtration. The deep red solid was washed with ice water and air-dried using suction filter. The solid was further dried under high vacuum for several hours. The red powder was heated at 170° C. using oil bath until gas evolution was no longer observed. Dark colored residue was purified by silica gel chromatography to yield 380 mg of (19) (37%). IR (cm−1, neat) 2927, 1634, 1521, 1465, 1400, 1336, 1282, 1249, 1091, 1H NMR (200 MHz CDCl3) δ 8.32 (d, J=2.8 Hz, 1H), 7.4–7.6 (m, 4H), 6.67 (d, J=5.0 Hz, 1H), 3.04 (s, 3H), 2.84 (s, 3H). Anal. (C15H12ClFN2O3S) C, H, N.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13](=[NH:15])[NH2:14].O=[C:17]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40](C(C)(C)C)[N:39]=[N:38][N:37]=2)=[CH:26][CH:25]=1)[C:19](OC)=[O:20]>>[CH2:45]([C:17]1[NH:14][C:13]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:15][C:19](=[O:20])[C:18]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2-c2nnnn2C(C)(C)C)cc1)C(=O)OC
Reactant: N=C(N)CCc1ccc2ccccc2c1
Product: CCCCc1[nH]c(CCc2ccc3ccccc3c2)nc(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
Following example 4.2, a mixture of 1.75 g of 3-(napht-2yl)propanimidamide and 3.3 g of methyl 3-oxo-2-[[2'-(1-[1,1-dimethylethyl]-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]heptanoate is heated at 100° C., for 3.50 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 2.9 g of the product in the form of a pale yellow paste. 1.5 g of the foregoing product are dissolved in a 30% solution of bromhydric acid in acetic acid. It is heated at 90° C., for 5 hours and evaporated under vacuum. The residue is taken up with dichloromethane. The organic phase is washed with water and dried on sodium sulfate. The solvent is evaporated to give 1.1 of the product in the form of a beige powder. The crude product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 0.63 g of the product in the form of a white powder.
Reaction SMILES: NC[C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][N:17]3[C:22](=[O:35])[CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[CH:9]=[N:8]1.BrC1C=[N:42]N(CC2C=C(C=CC=2)CNC(=O)OC(C)(C)C)C=1.BrC1C=CC=C2C=1CCCN2C(=O)CCCOC1C=CC=C(C)C=1C.CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(B3OC(C)(C)C(C)(C)O3)C=CC=2)CCC1)=O.CC1(C)C(C)(C)OB(C2C=NN(CC3C=C(NC(=O)OC(C)(C)C)C=CC=3)C=2)O1>>[NH2:42][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][N:17]3[C:22](=[O:35])[CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[CH:9]=[N:8]1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(CN)c5)c4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)NCc1cccc(Cn2cc(Br)cn2)c1
Agent: CC(C)(C)OC(=O)Nc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(N)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-(1-(3-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that tert-butyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzylcarbamate was replaced by 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one and 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one was replaced by tert-butyl 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)phenylcarbamate. LCMS, [M+H]+=495.4.
Reaction SMILES: C([NH:4][C:5]1[N:10]([O:11]C(=O)C)[C:9](=[NH:15])[N:8]=[C:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1)(=O)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:4][C:5]1[N:10]([OH:11])[C:9](=[NH:15])[N:8]=[C:7]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:6]=1
Reactant: C1CCNCC1
Reactant: CC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(=N)n1OC(C)=O
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Temperature: 25 °C

Procedure:
76 g (0.2 mole) of 6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidine are added to 760 ml of anhydrous piperidine at a temperature of 0° to 5° C. while stirring. The mixture is stirred at the same temperature for additional 2 hours, then let to warm to room temperature and stirred for additional 24 hours. The piperidine is distilled off under reduced pressure, 500 ml of water are added to the residue, then the mixture is left to stand in the refrigerator overnight. The precipitate is filtered, washed with water and filtered by strong suction. The filter cake is washed by suspending it 3 times with 50 ml of ether each and dried to give the aimed product in a yield of 23.0 g (55%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C@H:18]1[O:23][CH2:22][C@@H:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@@H:34]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:8])=[O:4].C(Cl)Cl.[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78]>>[NH:20]1[C@H:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@@H:34]([NH:48][C:49](=[O:50])[O:51][CH3:52])[CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:22][O:23][C@H:18]([CH2:17][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:61]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH2:19]1.[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CCc2ccccc2NC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CO[C@H](CCc2ccccc2NC(=O)[C@@H](NC(=O)OC)C(c2ccccc2)c2ccccc2)CN1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-Butyl(2R,5R)-2,5-bis {2-[2-({(2S)-2-[(methoxycarbonyl)amino]-3,3-diphenyl propanoyl}amino)phenyl]ethyl}morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: N=C=N.[F:4][C:5]([F:43])([F:42])[C:6]1[CH:7]=[C:8]([C:16]2([C:38]([F:41])([F:40])[F:39])[O:20][N:19]=[C:18]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]([NH:33][CH2:34][C:35]([OH:37])=O)=[O:32])=[CH:23][CH:22]=3)[CH2:17]2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.[F:44][C:45]([F:49])([F:48])[CH2:46][NH2:47]>ClCCl>[F:4][C:5]([F:42])([F:43])[C:6]1[CH:7]=[C:8]([C:16]2([C:38]([F:40])([F:41])[F:39])[O:20][N:19]=[C:18]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([C:31]([NH:33][CH2:34][C:35](=[O:37])[NH:47][CH2:46][C:45]([F:49])([F:48])[F:44])=[O:32])=[CH:23][CH:22]=3)[CH2:17]2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NCC(F)(F)F
Agent: N=C=N
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PS-Carbodiimide (400 mg, 123 mmol/g, Argonaut Technologies, Inc.) was added to a stirred mixture of N-[[4-[5-[3,5-bis(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine (i.e. the product of Step C, 140 mg) and 2,2,2-trifluoroethylamine (0.038 mL) in dichloromethane (3 mL) at room temperature. The mixture was stirred at room temperature overnight, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with ethyl acetate/hexanes to provide the title compound (115 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.77 (d, 1H), 8.16 (d, 1H), 8.13 (s, 2H), 8.01 (s, 1H), 7.51-7.60 (m, 3H), 7.46 (t, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 4.31 (d, 1H), 4.23 (d, 2H), 3.83-3.92 (m, 3H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:37]([Cl:38])=[CH:36][CH:35]=[C:34]([Cl:39])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:34]([Cl:39])=[CH:35][CH:36]=[C:37]([Cl:38])[C:30]=3[Cl:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1c(Cl)ccc(Cl)c1Cl
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4c(Cl)ccc(Cl)c4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3,6-trichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 571.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.