Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([NH:9][C:10]2=O)[CH2:7]3)=[CH:4][C:3]=1[F:15].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[Cl:17])[CH2:7]3)=[CH:4][C:3]=1[F:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NC2CC(C2)c2cc(F)c(Br)cc21
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cc2c(cc1Br)C(Cl)=NC1CC2C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Into a 20000-mL 4-necked round-bottom flask was placed a solution of 5-bromo-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one (800 g, 2.96 mol, 1.00 equiv) in toluene (10000 mL), followed by the addition of PCl5 (1540 g, 7.40 mol, 2.50 equiv) in several batches at 25° C. over 1 hour. The resulting solution was heated to reflux for 5 hr, cooled to room temperature and diluted with 5000 mL of ether. The solids were collected by filtration and dissolved in 10000 mL of ether. The resulting mixture was washed with 5000 mL of ammonia (10%), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 700 g (82%) of 5-bromo-8-chloro-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(OCC)(=O)C>C1CCCCC1>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(CCc2ccccc2)C(=O)OCc2ccccc2)CSC[C@H]1c1cccs1

Procedure:
282 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 16(g)] were N-alkylated with 684 mg of benzyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane, to separate it into two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: Fc1cccc(C[Zn+])c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cccc(F)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-fluoro-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 7): tR=0.98 min; Mass spectrum (ESI+): m/z=523 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[C:42]([Cl:45])(=[O:44])[CH3:43]>CN1C(=O)CCC1>[C:42]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:44])[CH3:43].[ClH:45]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and acetyl chloride (0.022 mL, 0.3 mmol). The mixture was stirred at RT for 15 min and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C26H28FN5O2: 462.5. NMR (CD3OD): 8.12 (1H, s), 7.37 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.28 (1H, m), 7.18 (1H, m), 7.15-7.10 (3H, m), 5.88 (1H, s), 4.69 (1H, m), 4.51 (2H, s), 4.06 (1H, m), 3.24 (1H, m), 2.89 (1H, m), 2.73 (1H, m), 2.15 (3H, s), 1.92 (2H, m), 1.66 (2H, m) ppm.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:25])=[CH:17][CH:16]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)COc1ccc(-c2ccccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccccc2F)nc1)Nc1ccccn1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.25 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 28.1 mg (0.3 mmol) of 2-aminopyridine. Yield: 28 mg.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].CNC.Cl.[CH:41]1([C:44]2[CH:45]=[C:46]([CH2:51][NH2:52])[CH:47]=[CH:48][C:49]=2[F:50])[CH2:43][CH2:42]1.C(N(CC)CC)C>C(O)C>[CH:41]1([C:44]2[CH:45]=[C:46]([CH:47]=[CH:48][C:49]=2[F:50])[CH2:51][NH:52][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:36])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:35])[C:18]=2[OH:26])=[O:23])[CH2:42][CH2:43]1
Reactant: NCc1ccc(F)c(C2CC2)c1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)c(C3CC3)c2)c(O)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A suspension of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.025 g, 0.050 mmol) and dimethylamine (0.050 mL, 0.101 mmol) (2 M in methanol) in ethanol (1 mL) was stirred at 50° C. for 1 h. Added to the mixture were (3-cyclopropyl-4-fluorophenyl)methanamine hydrochloride salt (0.025 g, 0.126 mmol) and triethylamine (0.070 mL, 0.504 mmol) and the mixture stirred at 90° C. for 5 h. The mixture was cooled to room temperature and concentrated. The brown residue was purified by preparative HPLC: Solvent A=10% ACN/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% ACN/10% H2O/0.1% trifluoroacetic acid; Start % B=0; Final % B=100; Gradient time=20 min; Stop time=23 min; Column=Sunfire 19×100 mm, C18, 5 μm. The resulting purple solid was triturated with hot methanol to give the title compound as a white solid (6.0 mg, 21% yield). 1H NMR (500 MHz, CDCl3) δ: 12.03 (1 H, s), 8.56 (1 H, t, J=5.49 Hz), 8.15 (1 H, s), 7.11-7.20 (1 H, m), 6.85-7.01 (2 H, m),4.49 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.97 Hz), 3.28 (3 H, s), 2.91 (3 H, s), 2.42-2.65 (3 H, m), 2.01-2.18 (3 H, m), 1.86-2.00 (2 H, m), 1.71 (2 H, ddd, J=13.28, 6.56, 6.41 Hz), 0.90-1.02 (2 H, m), 0.67-0.80 (2 H, m). LCMS (M+H) calcd for C26H31FN5O5: 512.23; found: 512.24.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Li+].[Li+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(O)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
To a solution of 2,5-dihydroxybenzaldehyde (10.41 g, 75.4 mmol) in 100 mL of DMF was added lithium carbonate (16.71 g, 226 mmol), followed by benzyl bromide (13.5 mL, 113 mmol). The solution was warmed to 60° C. and stirred for 30 hours. The reaction was poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown oil which was used without further purification.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH3:7])=[C:2]=[S:3].[CH:8]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH2:4]([NH:1][C:2]([NH:15][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:3])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCN=C=S
Reactant: NC1CCCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=S)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution prepared by dissolving 1-isothiocyanatobutane (3.0 ml, 26.0 mmol) in dichloromethane (5 ml) was slowly added to a solution prepared by dissolving 1-cycloheptylamine (3.3 ml, 26.0 mmol) in dichloromethane (20 ml) at 0° C. for 15 minutes. Triethylamine (7.3 ml, 52.1 mmol) was added to the mixed reaction solution and stirred at room temperature for 2 hours. After confirming completion of the reaction, distilled water (10 ml) was added to the reaction solution, and 1N of an HCl aqueous solution was added to neutralize. After separating an organic layer, a aqueous layer was extracted over dichloromethane (3×20 ml), and the organic layer was dried on sodium sulfate anhydrous, filtered and concentrated. The concentrated organic layer was purified by flash column chromatography (hexane:ethylacetate=3:1), thereby obtaining a target compound as a yellow liquid (4.1 g, 68%). The compound was used in the subsequent reaction.
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[CH2:2]([NH:6][C:15]1[CH2:19][S:18][C:17](=[O:20])[N:16]=1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCCN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
To a solution of but-3-yn-1-amine hydrochloride (4.88 g) and triethylamine (6.44 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.08 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.95 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9]O)=[C:4]([F:11])[CH:3]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][Cl:14])=[CH:6][C:7]=1[F:8]
Reactant: OCc1cc(F)c(Cl)cc1F
Reactant: O=S(Cl)Cl
Product: Fc1cc(CCl)c(F)cc1Cl
Temperature: 100 °C
Yield: 34 %

Procedure:
Step B A mixture of (4-chloro-2,5-difluoro-phenyl)-methanol (5.5 g, 32 mmol) in thionyl chloride (25 mL) was heated at refluxing (100° C.) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 1-chloro-4-chloromethyl-2,5-difluoro-benzene as a yellow oil (2.1 g, 34%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[C:15]1([CH3:34])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[B:23]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33])F>CCCCCC.C(OCC)C>[Br:13][C:11]1[CH:12]=[C:7]([B:23]([C:25]2[C:26]([CH3:33])=[CH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])[C:16]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=2[CH3:34])[CH:8]=[C:9]([Br:14])[CH:10]=1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(C)c(B(c2cc(Br)cc(Br)c2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
6.25 ml (0.01 mol) of 1.6M butyllithium in hexane are added over 5 minutes at -78° C. to a suspension of 3.14 g (0.01 mol) of 1,3,5-tribromobenzene in 50 ml of diethyl ether. The reaction mixture is stirred at -78° C. for 2 hours, during which a yellow-orange suspension is produced. 2.68 g (0.01 mol) of solid dimesitylfluoroborane are added, and the reaction mixure is warmed to room temperature over about one hour. The mixture is then diluted with 50 ml of hexane and cooled to 0° C. The solid produced is filtered, washed several times with cold hexane and then washed with water and, finally, with methanol, until the solid is colourless. Drying gives 3.54 g (0.0073 mol; i.e. 73% of theory) of a white solid (1,3-dibromo-5-dimesitylborylbenzene). Following purification by chromatography (hexane; SiO2) a melting point of 190°-191° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:18]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:13])[CH2:19]2)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: C[C@H]1CNCCN1
Reactant: Clc1nnc(Cl)c2cnccc12
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1,4-dichloropyrido[3,4-d]pyridazine 3 (0.500 g, 2.50 mmol) in NMP (2.5 ml) was added (S)-2-methylpiperazine (0.300 g, 3.00 mmol). The reaction was stirred at 25° C. for 2 h. After one hour reaction contents were diluted with water (20×) and extracted with 10% MeOH in CH2Cl2 (3×25 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 5% MeOH in CH2Cl2) afforded (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 plus 10-15% substitution at the 4-position. 1H NMR (CDCl3) δ 9.48 (s, 1H), 9.03 (d, J=5.5 Hz, 1H), 7.94 (d, J=5.5 Hz, 1H) 3.96 (m, 2H), 3.11-3.88 (m, 5H), 2.93 (dd, J=12.8, 10.4, 1H). MS (calc'd) 263.1 (M+H, found) 264.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:41])[CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)Cc3ccccc3)cc1)N2
Yield: 81 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (80 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol) in dichloromethane (5 mL) was added 2-phenylacetyl chloride (0.05 mL, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 3,3-dimethyl-2-(4-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 90 mg, yield: 81%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>ClCCl>[O:25]=[C:22]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)[CH:23]=[CH2:24]
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCc1ccc(CC(=O)OCC)cc1
Reaction time: 0.75 h

Procedure:
A solution of Ethyl 4-[aminomethyl]benzeneacetate (4.12 g) in anhydrous dichloromethane (60 ml) containing triethylamine (3.0 ml), was added over 20 min to a cold (-15°) stirred solution of acryloyl chloride (1.73 ml) in dry dichloromethane (50 ml) and stirring was continued for 0.75 h. After washing the dichloromethane solution with 8% aqueous sodium bicarbonate soln (2×50 ml) and drying (MgSO4), the organic solvent was removed by rotary evaporation to yield a a solid (approximately 6 g) which was triturated with cyclohexane to give the title compound as a solid (4.1 g) m.p. 93°-95°.
Reaction SMILES: O.NN.[O:4]=[C:5]1[C@@H:11]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][S:9][CH:8]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]1[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CO>[NH2:12][C@H:11]1[CH2:10][S:9][CH:8]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:5]1=[O:4]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SC[C@H](N2C(=O)c3ccccc3C2=O)C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CN1CC(c2cccs2)SC[C@H](N)C1=O
Reaction time: 48 h
Yield: 90.2 %

Procedure:
7 ml of hydrazine hydrate were added to a suspension of 34.1 g of t-butyl α-[5-oxo-6(R)-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] in 340 ml of methanol, to form a homogeneous solution. This was left standing for 2 days at room temperature, and then the resulting precipitate was filtered off. The filtrate was condensed by evaporation under reduced pressure, and then 200 ml of methylene chloride were added to the residue. The mixture was stirred and insoluble matter was filtered off. The filtrate was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was evaporated off. The residue was crystallized by adding diisopropyl ether containing a small amount of hexane, to yield 22.3 g of the title compound, melting at 81°-82° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[F-].[Cs+].[CH:15]1([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CS(C)=O>[CH:15]1([CH:21]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Reactant: O=C(C=CC1CCCCC1)c1cccc(O)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccco1)C1CCCCC1)c1cccc(O)c1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl)ethylene (1.66 g, 9.1 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.41 g, 2.7 mmol) were added to a suspension of 3-cyclohexyl-1-(3-hydroxyphenyl)-2-propen-1-one on Wang resin (2.6 g, 1.82 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% ACOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 2.7 g of 3-cyclohexyl-1-(3-hydroxyphenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[NH2:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[CH2:49][CH:48]([NH:53][C:54](=[O:59])[C:55]([F:58])([F:57])[F:56])[CH2:47]2.Cl.C(OCC)C>CC(O)C>[F:58][C:55]([F:56])([F:57])[C:54]([NH:53][CH:48]1[CH2:47][C:46]2[C:50](=[CH:51][CH:52]=[C:44]([NH:43][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:29]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)[CH:45]=2)[CH2:49]1)=[O:59]
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: Nc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(NC(=O)C(F)(F)F)C4)n2)c1
Yield: 37.3 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (109 mg, 0.25 mmol) (see Example 2, step B) and N-(5-amino-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (72 mg, 0.30 mmol) were combined in i-PrOH (2 mL) and 1M hydrochloric acid in diethyl ether (25 μL, 0.025 mmol) and heated at 180° C. in the microwave reactor for 20 min. The reaction product was concentrated and purified directly by silica gel flash column chromatography (30-100% EtOAc in hexanes). Purification yielded 61 mg (38%) of a brown oil. ES-LC/MS m/z=654 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:11][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:10])[CH3:9]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.35 g, 6.28 mmol) in anhydrous DMF (16 mL) was treated in several portions with sodium hydride (377 mg of 60% in oil, 226 mg, 9.42 mmol) followed by stirring at room temperature for 30 min. The mixture was then treated with methyl bromo-acetate (871 μL, 1.45 g, 9.48 mmol) dropwise (solution became warm after addition was complete) followed by stirring at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (4×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a nearly colorless solid, which was purified by column chromatography on silica gel, eluting with 20-100% ethyl acetate in hexanes. These procedures afforded the title compound as a colorless solid (1.47 g, 82%).