Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39](S(C)(=O)=O)[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:9]3[CH:8]=[C:7]([CH:21]4[CH2:23][CH2:22]4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:10]=3)[CH2:16][CH2:15]2)[N:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)c1nccc(OCc2ccccc2)n1
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCO)CC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCOc3nccc(OCc4ccccc4)n3)CC2)n1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
0.5 g of 3-[4-(2-tert-Butyl-6-cyclopropyl-pyrimidin-4-yl)-piperazin-1-yl]-propan-1-ol (1.57 mmol) were dissolved in 5 ml of tetrahydrofuran. 1.5 ml of n-butyllithium (15% in hexane) were added to the mixture at 0° C. Stirring was continued for 30 min and then 0.45 g of 4-benzyloxy-2-methanesulfonyl-pyrimidine (1.7 mmol) dissolved in 5 ml of tetrahydrofuran were added. The reaction was stirred overnight at room temperature and for an additional 2 h at 40° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (0-3%) as eluent to yield 0.6 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C@H:55]1[CH2:60][CH2:59][CH2:58][CH2:57][C@H:56]1[OH:61]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][C:9]([C:10]([NH:53][CH2:54][C@@H:55]3[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:56]3[OH:61])=[O:12])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Reactant: NC[C@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@@H]1CCCC[C@@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
6-Cyclopropylmethoxy-5-(4-fluoro-phenyl)-nicotinic acid (0.50 g, 2 mmol) was dissolved in DMF (20 mL). To the solution was added TBTU (0.62 g, 2 mmol), N,N-diisopropylethyl amine (1.5 mL, 9 mmol) and cis-2-aminomethyl-1-cyclohexanol (317 mg, 2 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 585 mg of the title compound as a colorless solid, MS (ISP) 399.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1.[CH:18]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19]1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1.[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:22](=[O:23])[NH:21][CH:18]3[CH2:20][CH2:19]3)[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: O=C=NC1CC1
Agent: CCN1CCC(O)N(c2nnc(OC)s2)C1=O
Solvent: CCN(CC)CC
Product: CCN1CCC(OC(=O)NC2CC2)N(c2nnc(OC)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and cyclopropyl isocyanate (3.5 ml; 0.07 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-cyclopropylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Br-].[Br-].[Zn+2].C(O)C>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][C:6]=1[CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1N

Procedure:
Charge 5% platinum(S)/charcoal (2.5 g), and ethyl 1-(5-chloro-2-nitrobenzyl)-4-methyl-1H-pyrrole-2-carboxylate (16.0 g, 49.57 mmoles) to a 500 mL Parr bottle. Add ethanol (200 mL) then zinc dibromide (0.22 equiv; 2.46 g, 10.91 mmoles) and place the mixture under hydrogen at 275.8 kPa and hydrogenate at room temperature overnight, monitoring formation of a partially hydrogenated intermediate. Remove the Parr bottle, heat gently in a water bath to dissolve the crystallized material, and filter through celite. Combine with the filtrate from an identical run and evaporate to give ethyl 1-(2-amino-5-chlorobenzyl)-4-methyl-1H-pyrrole-2-carboxylate an off-white solid. Place under high vacuum to remove residual ethanol to give the material (35 g, quantitative). MS (m/z): 293.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)=[O:29])=[C:23]([C:39]#[N:40])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[C:39]([C:23]1[CH:22]=[C:21]([CH:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:29])#[N:40]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3cccc(C#N)c3)c(C#N)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(NC(=O)Nc2ccc(C3CNCCO3)cc2C#N)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a stirred solution of trifluoroacetic acid (22 μl) in water (3 ml) was added a solution of (RS)-2-{3-cyano-4-[3-(3-cyano-phenyl)-ureido]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (13 mg) in acetonitrile (1.5 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(2-cyano-4-morpholin-2-yl-phenyl)-3-(3-cyano-phenyl)-urea (6 mg, 52%) as a light brown solid. MS (ISP): 348.1 ([M+H]+).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C@H:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][C@H:18]3[CH2:29][C:30]([O:32]CC)=[O:31])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3]>Cl>[ClH:1].[ClH:1].[ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C@H:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C@H:18]3[CH2:29][C:30]([OH:32])=[O:31])[CH2:15][CH2:16]2)=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C(=N)N)cc2)CC1
Agent: Cl
Product: N=C(N)c1ccc(N2CCN([C@H]3CCN(CC(=O)O)C[C@H]3CC(=O)O)CC2)cc1
Yield: 165.8 %

Procedure:
280 mg of (+)-cis-diethyl 4-[4-(4-amidinophenyl)-1-piperazinyl]-1,3-piperidinediacetate hydrochloride was dissolved in 10 ml of 1N-hydrochloric acid and refluxed for 48 hours. The reaction liquid was distilled, and the resulting residue was purified by ODS column chromatography (using an eluent of water) to obtain 160 mg of (+)-cis-4-[4-(4-amidinophenyl)-1-piperazinyl]-1,3-piperidinediacetic acid trihydrochloride (98.2% e.e.).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[O:39]1[CH2:44][CH2:43][N:42]([S:45]([C:48]2[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][CH:53]=2)(=[O:47])=[O:46])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:50]4[CH:51]=[CH:52][CH:53]=[C:48]([S:45]([N:42]5[CH2:43][CH2:44][O:39][CH2:40][CH2:41]5)(=[O:47])=[O:46])[CH:49]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: O=S(=O)(c1cccc(B(O)O)c1)N1CCOCC1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(S(=O)(=O)N5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.34 mmol) was treated with (3-(morpholinosulfonyl)phenyl)boronic acid (140 mg, 0.52 mmol), tetrakis(triphenylphosphine)palladium(0) (195 mg, 0.5 mmol), aqueous solution 2M of sodium carbonate (260 μl, 0.5 mmol) and 5 ml N,N-dimethylformide as a solvent according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to give 90 mg (58% yield) of the title compound. Purity 80%.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57]>[Pd].O1CCCC1>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[N:9]=[CH:8][CH:7]=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(N2CCn3c(cc4c3CCCC4)C2=O)ccnc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1cc(-c2nccc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 104b (658 mg, 1.0 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2(1H)-one 101l (622 mg, 2.0 mmol), Pd (dppf) Cl2 (65 mg, 0.08 mmol), K3PO4.3H2O (361 mg, 1.6 mmol), and tetrahydrofuran (40 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 104c as a yellow solid (400 mg, 63%). MS: [M+H]+ 635.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[C:11]([N:6]1[C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=3)=[CH:3][C:4]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:13])[CH3:12]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCCOc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(C)=O)ncc1Cl

Procedure:
1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (97 mg, 0.47 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (169 mg, 0.536 mmol), and 10-Camphorsulfonic acid (16 mg, 0.070 mmol) in Isopropyl alcohol (4 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was neutralized with MP-carbonate (0.3 mmol) and purified on silica gel (ISCO, 2×12 g, 0-100% EtOAc:Hex) to afford 2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as off white solids (122 mg, 53%). MP=226-228° C.; LCMS: 485 (M+H); 1H-NMR (DMSO): 9.51 (s, 1H), 9.42 (s, 1H), 9.56 (m, 1H), 8.21 (s, 1H), 7.49 (m, 2H), 7.42 (m, 1H), 7.36 (s, 1H), 7.17 (m, 1H), 7.05 (d, 1H, J=8.5 Hz), 4.54 (m, 1H), 4.32 (m, 1H), 3.55 (m, 1H), 2.74 (d, 3H, J=4.5 Hz), 1.92 (m, 1H), 1.71 (m, 4H), 1H obscured by solvent.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.[CH:28]1([CH2:31][O:32][CH2:33][CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]3[O:43][CH2:42]3)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50]>C(O)CC>[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50].[OH:43][CH:41]([CH:40]([CH2:46][C:47]1[CH:11]=[CH:10][CH:9]=[CH:49][CH:48]=1)[O:39][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][O:32][CH2:31][CH:28]2[CH2:29][CH2:30]2)=[CH:45][CH:44]=1)[CH2:1][NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:18][CH:19]=1)=[O:12].[OH:43][CH:41]([CH:40]([CH2:46][C:47]1[CH:19]=[CH:14][CH:15]=[CH:49][CH:48]=1)[O:39][C:38]1[CH:44]=[CH:45][C:35]([CH2:34][CH2:33][O:32][CH2:31][CH:28]2[CH2:30][CH2:29]2)=[CH:36][CH:37]=1)[CH2:42][NH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:18][CH:19]=1)=[O:12]
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCc2ccccc2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCCO
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCNCC(O)C(Cc2ccccc2)Oc2ccc(CCOCC3CC3)cc2)cc1
Yield: 116.1 %

Procedure:
In a manner similar to that of Example 1 (iii), 6-[4-(3-benzylaminopropionamido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (21.8 g) and 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (19.4 g) in n-propanol (200 ml) were stirred under reflux for 41/2 hours. The mixture was cooled and a solution of fumaric acid (6.96 g) in hot n-propanol (150 ml) added with stirring. Cooling (and seeding) and stirring overnight afforded 6-[4-[3-[2-hydroxy-3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-N-benzylpropylamino]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hemifumarate (31.05 g), m.p. 125°-8° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)(=O)[CH3:2].[NH2:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]=O>C(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:26][C:24]1[CH:25]=[C:18]2[C:19]([CH:20]=[CH:2][C:1]([C:4]3[CH:5]=[CH:6][C:7]4[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=4[CH:16]=3)=[N:17]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc2cc(C(C)=O)ccc2o1
Reactant: Nc1cc(Cl)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc2cc(-c3ccc4ccc(Cl)cc4n3)ccc2o1
Temperature: 200 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A mixture of 5-acetyl-2-methoxycarbonylbenzofuran (0.57 g), 2-amino-4-chlorobenzaldehyde (0.40 g) and p-toluenesulfonic acid monohydrate (0.04 mg) was stirred at 200° C. for 3 hours. After being cooled, the resulting mixture was dissolved in chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:20). The fractions containing object compound were combined and concentrated under reduced pressure to give 7-chloro-2-(2-methoxycarbonylbenzofuran-5-yl)quinoline (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.S(Cl)([Cl:16])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]([Cl:16])=[O:13]
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)Cc1cc(Cl)cc(Cl)c1Cl

Procedure:
A suspension of 6.0 grams (0.023 mole) of 2,3,5-trichlorophenylacetic acid in about 125 mL of carbon tetrachloride was stirred, and 5 mL of thionyl chloride was added. The reaction mixture was then warmed to reflux, where it was stirred for about 30 minutes. After this time the reaction mixture was concentrated under reduced pressure, yielding 6.4 grams of 2,3,5-trichlorophenylacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].[C:8]1([CH2:14][O:15][C:16]([N:18]2[CH:22]([CH2:23][CH2:24][CH:25]=[C:26]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]([O:29][CH3:30])=[O:28])[C:21](=O)[O:20]C2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH:5][C:21](=[O:20])[C@H:22]([CH2:23][CH2:24]/[CH:25]=[C:26](/[C:27]([O:29][CH3:30])=[O:28])\[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[NH:18][C:16]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:17]
Reactant: COC(=O)[C@@H](C)N
Reactant: COC(=O)C(=CCCC1C(=O)OCN1C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Product: COC(=O)/C(=C/CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
A mixture of 3.3 g of D-alanine methyl ester and 7.1 g of 46c is heated at 140° C. for 10 min, then another 1.6 g of D-alanine methyl ester is added. Heating is continued at 140° C. for an additional 10 min. After cooling to ambient temperature the crude product is chromatographed on silica gel using variable gradient hexane/ethyl acetate. Purified product (6.7 g) is recovered. The material is crystallized from hexanes-ether to give 5.8 g of the desired product 47c as a solid. NMR δ1.43(s,d,12H); 1.80-2.10(m,2H); 2.23-2.36(m,2H); 3.72(s,3H); 3.76(s,3H); 4.15-4.27(m,1H); 4.50-4.60(m,1H); 5.11(b s,2H); 5.76(b s,1H); 6.38(b s,1H); 6.47(b t,1H); 6.81(b s,1H); 7.34(m,5H); 13C-NMR: 17.82(--CHCH3 ; 24.33(--C H2 --CH2); 28.02(C(CH3)3); 30.99(--CH2CH=C); 47.94(--CHCH3); 52.17 (--OCH3); 52.29(--OCH3); 54.28(OCCHNH); 66.93(--CH2Ar); 80.43(--OC(CH3)3); 126.57(--HNC=C); 127.86(phenyl ring carbon); 127.94 (phenyl ring carbon); 128.12(phenyl ring carbon); 128.28(phenyl ring carbon); 135.98(phenyl ring carbon); 153.45(OCONH); 156.21(OCONH--); 165.13(--CONH--); 171.04(--CO2 --); 172.99(--CO2 --). IR(KBr, cm-1) 3300(s); 1720(s); 1690(s); 1650(s); 1510(s); MS(CI) m/z 522(MH)+ ; 466(MH--C4H8)+ ; 422(MH--C4H8CO2)+. MS(FAB) m/z 544(M+Na)+ ; 522(MH)+ ; 466(MH--C4H8)+ ; Anal Calcd: C, 57.57; H, 6.76; N, 8.06; Found: C, 56.98;H, 6.66; N, 7.88. [α]D26 -7±1; m.p. 120°-121° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]#[N:7])[CH2:3]1.N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:17]([O:1][C@@H:2]1[CH2:5][C@H:4]([C:6]#[N:7])[CH2:3]1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: N#C[C@H]1C[C@@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](C#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-3-hydroxy-cyclobutanecarbonitrile (500 mg, 5.15 mmol in DMF (3 mL) at room temperature was added imidazole (876 mg, 12.9 mmol) followed by TBDMS-Cl (854 mg, 5.66 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 10% EtOAc/hexanes to afford 890 mg (82%) of cis-3-(tert-butyldimethylsilanyloxy)-cyclobutanecarbonitrile as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.10-4.19 (m, 1H), 2.57-2.67 (m, 2H), 2.43-2.54 (m, 1H), 2.22-2.34 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])CCC.B(F)(F)F.[CH2:24]([CH:26]1[O:28][CH2:27]1)[Cl:25]>C1COCC1>[Cl:25][CH2:24][CH:26]([OH:28])[CH2:27][N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: ClCC1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(O)CCl)C(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
In a 50 0 ml round bottom flask with magnetic stirrer 4-Boc-piperazinone (5.08 g, 25.4 mmol) was dissolved in THF (100 mL) and cooled to −78° C. Butyllithium (1.6M in hexanes) (15.9 mL, 25.4 mmol) was added then and the mixture agitated for 30 minutes at −78° C. Boron trifluoride ethereate (3.19 mL, 25.4 mmol) was added slowly and then epichlorohydrin (1.99 mL, 25.4 mmol). The mixture was agitated for 1 hour at −78° C. and then allowed to warm up and agitated overnight. Reaction was quenched with saturated ammonium chloride, extracted three times with ethyl acetate, extracts washed with brine and evaporated. Purified by column chromatography on silica gel, eluting with 3% MeOH/CH2Cl2 to give the title compound (3.34 g, 45% yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[C:27][Si](C)(C)C)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]#[CH:27])[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC#C[Si](C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
In THF (7.8 ml)/methanol (7.8 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-trimethylsilyl-2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.78 g). To the solution was added 2N potassium hydroxide (7.8 ml), and the mixture was stirred at room temperature for 16 hours. pH was adjusted to approximate 4 with 6N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was washed with hexane/ethyl acetate (=8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.52 g).