Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:23])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCC=Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCC=Cc1ccc(F)cc1

Procedure:
A solution of 10-(4-fluoro-phenyl)-dec-9-enoic acid (230 mg, 0.87 mmol), oxalyl chloride (0.11 mL, 1.3 mmol), and N,N-dimethylformamide (one drop) in dichloromethane (3 mL) was stirred at room temperature for 2 hours, then volatile material was removed by distillation to afford 10-(4-fluoro-phenyl)-dec-9-enoyl chloride. This was redissolved in dichloromethane, then N,N-diisopropylethylamine (140 mg, 1.04 mmol) was added dropwise, followed by (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride. The reaction mixture was stirred at room temperature for 16 h, then washed with water. The organic layer was evaporated and the residue purified by preparative HPLC to afford (R)-4-dimethylamino-3-[10-(4-fluoro-phenyl)-dec-9-enoylamino]-butyric acid benzyl ester (100 mg, 24%), m/e=483.4 ([M+H]+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=O.[NH2:21][C@H:22]1[CH2:27][C:26]2[C:28]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH2:23]1>CN(C)C=O>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:28]2[C:26]3[CH2:27][C@H:22]([NH:21][C:18]([C:14]4[NH:13][CH:17]=[CH:16][CH:15]=4)=[O:20])[CH2:23][O:24][C:25]=3[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: O=C(O)c1ccc[nH]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc[nH]2)CO3)CC1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1,1′-carbonyldiimidazole (360 mg, 1.85 mmol) and pyrrole-2-carboxylic acid (225 mg, 2.03 mmol) in anhydrous N,N-dimethylformamide (8 mL) was stirred at 75° C. for 45 min. The mixture was allowed to cool, and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (457 mg, 1.85 mmol) in N,N-dimethylformamide (10 mL) was added. The reaction mixture was stirred for 7 days at room temperature under nitrogen. The solvent was removed in vacuo, and the residue was extracted with diethyl ether (50 mL) and water (20 mL). The aqueous layer was extracted with another portion of diethyl ether (50 mL). The combined ethereal layers were dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 90:10+0.5% conc. NH3) yielding the title compound as an oil. Evaporation with diethyl ether afforded 300 mg (48% yield) of the title compound as a white powder: mp sinters>96° C.; [α]21D−82.8° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 340 (10, M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13](Cl)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13]([NH:16][C:17]3[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=3[C:22]([NH2:24])=[O:23])=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1cccc2cc(C(=O)Cl)oc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1cc2cccc(OCC)c2o1

Procedure:
From 7-ethoxybenzofuran-2-carbonyl chloride (4.124 g, 20 mmol), 1 (1.82 g, 10 mmol), DMAP (32.5 mg, 0.27 mmol) and Et3N (2.02 g, 20 mmol) in anhydrous CH2Cl2 (65 mL) using the same procedure as for 3 the title compound was obtained as?a white solid; mp: 219-221° C.; 1H NMR (DMSO-d6) δ 0.86 (t, J=7 Hz, 3 H), 1.43 (t, J=7 Hz, 3 H), 1.56 (sxt, J=7 Hz, 2 H), 2.42 (t, J=7 Hz, 2 H), 3.91 (s, 3 H), 4.28 (q, J=7 Hz,2 H), 7.10 (d, J=6 Hz, 1 H), 7.26 (t, J=6 Hz, 1 H), 7.35 (d, J=6 Hz, 1 H), 7.50 (s, br. 1 H), 7.71 (s, 1 H), 7.76 (s, br. 1 H); MS (m/z): 371 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1([C:43]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[S:45][N:44]=2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>[I-].[K+].CN(C=O)C>[S:45]1[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:43]([N:37]2[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:41][CH2:42]2)=[N:44]1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (1.36 g) and DMF (40 ml) was added anhydrous potassium carbonate (0.3 g), diisopropylethyl amine (0.8 ml), 3-piperazinyl-1,2-benzisothiazol (1.26 g) and potassium iodide (27 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 12 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 20% triethylamine/ether) afforded 1.0 g of 5-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one as a foam. The product was flushed through alumina with dichloromethane. The hydrochloride was prepared by dissolving the free amine with menthanol and adding ethereal HCl. The salt was filtered and washed with pentane, m.p. 215° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)CCC1C=NC(C(C#N)(C)C)=C(Cl)C=1)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)O)CC1

Procedure:
The title compound was prepared analogously to step 5 of example B(29) where 4-(4-ethoxycarbonyl-butyl)-piperidine-1-carboxylic acid tert-butyl ester from step 3 above, was substituted in place of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-propionic acid ethyl ester in that example. 1H NMR (400 MHz, CDCl3): δ 1.07–1.39 (m, 7H), 1.45 (s, 9H), 1.59–1.70 (m, 4H), 2.33–2.38 (m, 2H), 2.64–2.68 (m, 2H), 4.09–4.12 (m, 2H). ESIMS (MH−): 284.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[C:44](=[O:45])[CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 3.35 mmol) in CH2Cl2 (25 mL), phenylacetyl chloride (0.53 mL, 4.02 mmol) and triethylamine (0.56 mL, 4.02 mmol) are added under N2 atmosphere at 0° C. The mixture is stirred 30 min at 0° C., then allowed to reach RT and further stirred for 1 h. The reaction mixture is diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 20:80 to 0:100) to give the title compound. TLC, Rf (CH2Cl2/MeOH 95:5)=0.4. MS (LC-MS): 526 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.71 min.
Reaction SMILES: COC(=O)[C:4]1[C:9](C)=[CH:8][C:7](C2C=CC=C(C(F)(F)F)C=2)=[N:6][C:5]=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.N1C=CC=C(B(O)O)C=1>>[CH3:44][C:28]1[CH:27]=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:25]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[N:30][C:29]=1[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1)=[O:32]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Agent: OB(O)c1cccnc1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cccnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless oil. MS: 495.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([O-:11])[CH:10]=1.[K+].Br[CH:25]([CH3:38])[C:26]([O:28][CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[O:27]>>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([CH:10]=1)[O:11][CH:25]([CH3:38])[C:26]([O:28][CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[O-]
Reactant: CCOP(=O)(COC(=O)C(C)Br)OCC
Agent: [K+]
Product: CCOP(=O)(COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
by using potassium 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenolate and diethyl (2-bromopropionyloxy)-methylphosphonate there is obtained diethyl [2-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]-propionyloxy]methylphosphonate, 1H-NMR (CDCl3 ; 400 MHz) 7.93 ppm (d, 1H), 7.79 ppm (d, 1H), 7.58 ppm (q, 1H), 7.21 ppm (d, 1H), 6.63 ppm (d, 1H), 6.49 ppm (q, 1H), 4.89 ppm (q, 1H), 4.45 ppm (m, 2H), 4.14 ppm (m, 4H), 1.74 ppm (d, 3H), 1.32 ppm (tt, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:33][CH2:32]2)[CH2:26][NH:27][CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24].C(N(CC)CC)C>CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:35][CH2:36]2)[CH2:26][N:27]([CH3:28])[C:14]([C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1CCCC2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc([N+](=O)[O-])cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
3-Nitro-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride [from 3-nitro-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.150 g , 6.78 mmol) and PCl5 (0.190 g, 8.48 mmol) in EtOAc (1.5 mL) as described in T. Nakayama, T. Okutome, R. Matsui, M. Kurumi, Y. Sakurai, T. Aoyama, S. Fujii, Chem. Pharm. Bull. 32(10) 3968 (1984)] was dissolved in EtOAc (2 mL) and added to a stirred solution of N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine (0.3075 g, 0.678 mmol), triethylamine (0.124 mL, 0.892 mmol) and EtOAc (3.1 mL) and the mixture stirred overnight at ambient temperature. The reaction mixture was washed with 10% aqueous HCl, 5% aqueous NaOH and brine solutions, dried (MgSO4) and the solvent removed in vacuo to yield the title compound (0.168 g, 38%) which was converted to the citrate salt MS: m/z 656 (M+H). Analysis for C34H39Cl2N3O4S.C6H8O7.2.0H2O: calculated: C, 54.30; H, 5.81; N, 4.75; found: C, 54.10; H, 5.55; N, 4.55.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(Br)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>C1C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17]
Reactant: O=Cc1c(O)cc(O)cc1O
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=Cc1c(O)cc(O)cc1O
Yield: 65.4 %

Procedure:
2,4,6-Trihydroxybenzaldehyde (17.69 g, 0.115 mole) was added to a solution of N-tert-butyl hydroxylamine (14.32 g, 0.161 mole) in benzene (250 mL). p-Toluenesulfonic acid (15 mg) was added and the reaction vessel fitted with a Dean-Stark trap. The reaction was heated at reflux for 88 hours under nitrogen and then diluted with 500 mL of ethyl acetate. The solution was washed with water, brine and dried over sodium sulfate. The product was recrystallized from ethanol/water and then dried in vacuo for 2 hr at 35° C. to provide 16.95 g (65.5% yield) of the title compound. The product had a melting point of 189.9-190.3° C. and an Rf on silica gel TLC (50% hexane, 45% ethyl acetate, 5% methanol) of 0.31 (2,4,6-trihydroxybenzaldehyde Rf=0.47).
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:28])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:27])[O:16][C@@H:17]1[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]1[CH:24]([CH3:26])[CH3:25])=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[NH2:8][C:9]1([CH3:28])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:27])[O:16][C@@H:17]1[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]1[CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-{[(tert-butoxy)carbonyl]amino}-2-methylcyclopentyl)carbamate (25.2 g, 63.5 mmol) in DCM (100 ml) was added HCl in 1,4-dioxane (4 M, 60 ml, 240 mmol). The reaction mixture was stirred at room temperature for 18 hours and then further HCl in 1,4-dioxane (4 M, 20 ml, 80 mmol) was added and the stirred for an additional 24 hours at room temperature. The reaction was concentrated in vacuo and purified by SCX chromatography (2M ammonia in methanol). The resulting residue was suspended in DCM/methanol and to this was added HCl in 1,4-dioxane (4 M, 10 ml, 40 mmol) and stirred for 2 hours. The reaction was concentrated in vacuo and further evaporated from diethyl ether and then methanol to afford the title compound as a mixture of trans-amino compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>CN(C)C=O.O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: COc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CSc1ccccc1OC)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.6 %

Procedure:
To a suspension of 2-methoxybenzenethiol (10 g, 71.4 mmol) and potassium carbonate (20 g, 143 mmol) in dry N,N-dimethylformamide (100 mL) was added dropwise over 20 mins a solution of bromoacetaldehyde diethyl acetal (10.3 mL, 71.4 mmol) in dry N,N-dimethylformamide (50 mL). The resulting suspension was allowed to stir at room temperature for 45 mins before being diluted with water (500 mL) and extracted with hexane (200 mL). The organic phase was further extracted with brine (4×100 mL), with the resulting organic phase being dried (MgSO4) and the solvent removed in vacuo to give a pale yellow oil (18.6 g) which was ca 95% pure. This material was further purified by flash chromatography eluting silica gel with hexane:ether [10:1] to give a colourless oil (18 g, 98%). δH (300 MHz, CDCl3) 7.34 (1H, d, Ar), 7.2 (1H, m, Ar), 6.92–6.80 (2H, m, Ar), 4.62 (1H, t, J=7 Hz, CH(OEt)2), 3.85 (3H, s, OCH3), 3.70–3.42 (4H, m, OCH2CH3), 3.10 (2H, d, J=7 Hz, SCH2), 1.12 (6H, t, J=7 Hz, OCH2CH3).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][N:11]([CH3:18])[C:12](=[O:17])[CH2:13][C:14]([CH3:16])=O.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH3:4][C:3]1([CH3:5])[S:6][C:14]([CH2:13][C:12]([N:11]([CH3:18])[CH3:10])=[O:17])([CH3:16])[NH:1][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)CC(=O)N(C)C
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CN(C)C(=O)CC1(C)NC(C(=O)O)C(C)(C)S1
Yield: 65.9 %

Procedure:
A suspension of 2.00 g (13.4 mmoles) of D-penicillamine and 1.73 g (13.4 mmoles) of N,N-dimethylacetoacetamide in 15 ml of dry benzene, and 0.6 g of anhydrous magnesium sulfate was refluxed for 3.5 hours under a stream of argon. The reaction mixture became clear and then the solvent was distilled off. The resulting residue was dissolved in hot methyl alcohol. Insolubles were removed by filtration and the solvent was again distilled off. The residue was crystallized from chloroform and further recrystallized from ethyl alcohol-ether to give 2.3 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]([CH3:44])([C:41](O)=[O:42])[C:37]2=[O:45])=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:41]([C:38]2([CH3:44])[CH2:39][CH2:40][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:37]2=[O:45])=[O:42])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: CC1(C(=O)O)CCN(c2ccc(F)cc2)C1=O
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)C5(C)CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)CC1
Yield: 84 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-(4-fluorophenyl)-3-methyl-2-oxopyrrolidine-3-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 26 mg (84%) of the desired product. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 66 mg (62%) of the desired product. LRMS (APCI pos) m/e 616.1 (M+1). 1H-NMR (400 MHz, CD3OD) δ 8.49 (d, 1H), 7.87 (dd, 1H), 7.68 (m, 2H), 7.59 (s, 1H), 7.45 (m, 1H), 7.36 (t, 1H), 7.15 (t, 2H), 6.69 (d, 1H), 4.25 (t, 2H), 3.91 (m, 2H), 3.68 (s, 2H), 2.79 (m, 6H), 2.56 (m, 2H), 2.30 (s, 3H), 2.18 (m, 2H), 1.66 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −119.0, −130.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][C:13]=3F)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.C1OCCOCCOCCOCCOCC[O:21][CH2:20]1.C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][C:13]=3[O:21][CH3:20])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cn1c(=O)c2cncc(F)c2c2ccc(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cncc2c(=O)n(C)c3cc(Cl)ccc3c12
Temperature: 100 °C
Yield: 973.3 %

Procedure:
To the solution of 8-chloro-1-fluoro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (40 mg, 0.152 mmol), prepared as described in Example 85, Part E, in MeOH (0.2 mL) in a microwave vial, 18-crown-6 (4.03 mg, 0.015 mmol) and sodium methoxide (32.9 mg, 0.152 mmol) in methanol were added and heated in a microwave oven at 100° C. for 30 min. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8-chloro-1-methoxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (40 mg, 0.146 mmol, 96% crude yield) as a white solid. The material was carried forward without further purification. LC/MS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12ClN2O2 275.05]; LC/MS retention time (method D): tR=0.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[NH:23](/[N:24]=[C:17]1\[CH2:18][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][C:11]2[O:15][CH:14]=[C:13]([CH3:16])[C:12]\1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: COc1ccccc1C1CC(=O)c2c(C)coc2C1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1C1C/C(=N\NC(=N)N)c2c(C)coc2C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a mixture of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.19 g) and aminoguanidine hydrochloride (82 mg) were added ethanol (15 ml) and 6N hydrochloric acid (0.064 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-4-guanidinoimino-6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 46) (0.19 g).