Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][C:13](=[O:16])[C:12]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[F:18][C:19]1[CH:24]=[C:23]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][C:13](=[O:16])[C:12]=3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1COc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1COc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 98.9 %

Procedure:
Cesium carbonate (612 mg, 1.88 mmol) was added to a solution of 5-bromobenzofuran-3(2H)-one (200 mg, 0.939 mmol), (3-fluorophenyl)boronic acid (263 mg, 1.88 mmol) and toluene (20 mL) in a 50 mL Schlenk tube. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.01 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient), to afford 212 mg (99%) of 5-(3-fluorophenyl)benzofuran-3(2H)-one.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C(N(CC)C(C)C)(C)C.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([NH:43][C:44]([N:27]1[CH2:26][CH:25]=[C:24]([C:22]2[NH:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([NH:14][C:10]4[CH:9]=[C:8]5[C:13](=[CH:12][CH:11]=4)[N:5]([CH3:4])[N:6]=[CH:7]5)[C:16]=3[CH:23]=2)[CH2:29][CH2:28]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)NC(C)(C)C)CC5)cc34)ccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (166.8 mg, 0.3631 mmol, 1 eq) in anhydrous DMF (17 mL), N,N-diisopropylethylamine (DiPEA) (260 μL, 4.1 eq) was added at rt. The solution was then cooled to −20° C., after which tert-butyl isocyanate (36.5 mg, 0.368 mmol, 1 eq in anhydrous DMF (2 mL) was added. The solution was stirred at rt for 1 h. The reaction was cooled to 0° C., after which additional tert-butyl isocyanate (11.4 mg, 0.115 mmol, 0.3 eq) in anhydrous DMF (1 mL) was added. The reaction was stirred again at rt for 4 h. The reaction was quenched with MeOH, concentrated in vacuo, and dried under vacuum pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 1%→5%]. Fractions containing product were combined and concentrated in vacuo. The material was further purified by trituration in MeOH, yielding the title compound as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ=1.28 (s, 9H), 2.44 (s, br, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.99 (d, J=2.0 Hz, 2H), 4.03 (s, 3H), 5.77 (s, —NH), 6.40 (s, br, 1H), 6.75 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (s, 1H), 8.26 (s, 1H), 8.39 (s, 1H), 9.32 (s, —NH), 11.89 (s, —NH). MS (ES+): m/z 445.07 (100) [MH+]. HPLC: tR=2.29 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1ncccc1N

Procedure:
A solution of 6-chloro-3-nitropicolinamide (2.00 g, 9.91 mmol) in EtOAc/MeOH (1:1, 100 mL) is hydrogenated over 5% Pd-C (0.40 g) at 60 psi for 6 days, with additions of fresh catalyst after 2 and 4 days. After removal of the catalyst by filtration the solution is concentrated to dryness, to give 3-aminopicolinamide as an orange oil, which is used directly in the next step. The crude product is stirred under reflux with triethyl orthoformate (50 mL) for 42 h, during which time a tan precipitate forms. After cooling, the solid is filtered off, washed well with petroleum ether, and dried under vacuum to give 3H-pyrido[3,2-d]pyrimidin-4-one (1.27 g, 87%), mp 343-345° C. [Price, C. C. and Curtin, D. Y. J. Amer. Chem. Soc. 68, 914, 1946 report mp 346-347° C⟧
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH2:26])[CH2:23][CH2:22]2>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH:26][C:8]1[CH:7]=[CH:6][C:5]3[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=1)[CH2:23][CH2:22]2
Reactant: COc1cccc2c1C(N)CC2
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1cccc2c1C(Nc1ccc3c(N)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=306.4 (M+H+), was prepared in accordance with the general method of example 16 from 5-nitro-2-chloroquinoline and 7-methoxy-indane-1-ylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[O:10]1[CH2:14][CH2:13][CH:12]([CH:15]=O)[CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:15][CH:12]2[CH2:13][CH2:14][O:10][CH2:11]2)=[CH:4][N:3]=1
Reactant: O=CC1CCOC1
Reactant: Nc1cnc(Cl)nc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ncc(NCC2CCOC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To 2,4-dichloropyrimidin-5-amine (6.22 g, 38.0 mmol) in 16.5 mL of dichloromethane was added dry tetrahydrofuran-3-carbaldehyde (3.8 g, 38.0 mmol). The solution was cooled to 0° C. A solution of titanium tetrachloride (41.8 ml, 41.8 mmol) in 10 mL of dichloromethane was added slowly. The reaction mixture was stirred at for 2 hours. Sodium triacetoxyborohydride (24.13 g, 114 mmol) was added in 4 equal portions over about 10 minutes and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with water and extracted twice with methyl-t-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 8.2 g of 2,4-dichloro-N-((tetrahydrofuran-3-yl)methyl)pyrimidin-5-amine as a tan solid which was used without further purification. [M+H] found 249.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:9][CH2:8]1)=[O:6].[Li+].[OH-]>C1COCC1.O>[CH:19]1([C:10]2([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH:4]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:3]([OH:33])=[O:2])[CH2:8][CH2:9]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)C(Cc1ccc(F)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc(F)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-cylcohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-(4-fluorobenzyl)-3-oxo-propionic acid methyl ester, 57, (456 mg, 1 mmol) in THF/H2O (2:1) at RT is added LiOH (1.5 equiv.). The reaction is stirred at RT until the starting material is consumed. The solvent is removed in vacuo, and the residue is purified by reverse phase HPLC to provide the desired product.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([N:62]2[CH2:67][CH2:66][N:65]([C:68](=[NH:84])[N:69](C)[C:70](OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:64][CH2:63]2)=[O:61])[CH2:43]1>>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([OH:23])=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][NH:45][C@H:44]([C:60]([N:62]4[CH2:67][CH2:66][N:65]([C:68](=[NH:84])[NH:69][CH3:70])[CH2:64][CH2:63]4)=[O:61])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C(=N)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: CNC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CC1

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-2-[4-(methyl-4-nitrobenzyloxycarbonylamidino)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 104 as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24](O)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[NH2:29][CH2:30][CH2:31][C:32]#[N:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:33][CH2:32][CH2:31][C:30]#[N:29])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: N#CCCN
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NCCC#N)s3)C[C@H]2OC)nc1Cl
Yield: 79.9 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (75 mg, 0.18 mmol), 3-aminopropionitrile (14 mg, 0.20 mmol), WSC hydrochloride (111 mg, 0.58 mmol), HOBT (39 mg, 0.29 mmol), dichloromethane (1.5 mL) and DMA (1.5 mL), to obtain 69 mg of the title compound as a white solid (82%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH:19]=[O:20])=[CH:7]2.[CH3:21][Mg]Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH:19]([OH:20])[CH3:21])=[CH:7]2
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1C(C)O

Procedure:
Prepared according to Procedure K. To a mixture of 8-methyl-2-o-tolylquinoline-3-carbaldehyde (434 mg, 1.7 mmol) in THF (6 mL) at 0° C. was added dropwise a solution of MeMgCl (3M, 2 eq, 1.1 mL) and the reaction was stirred over night before quenched with NH4Cl saturated solution. The mixture was extracted with EtOAc (2×10 mL) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: EtOAc/hexane, 1/1) to provide 1-(8-methyl-2-o-tolylquinolin-3-yl)ethanol as a white solid. 1H-NMR (CDCl3) δ 8.34 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.48 (d, J=6.7 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.19-7.27 (m, 4H), 2.69 (s, 3H), 2.08 (s, 3H), 1.30 (m, 3H). Mass Spectrum (ESI) m/e=278 (M+1).
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.ClC(C)C>>[CH:2]([C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Cl
Reactant: c1ccc2ccccc2c1
Product: CC(C)c1cccc2ccccc12

Procedure:
Reaction was carried out as in Example 4, but using 2-chloropropane as the alkylating agent with a molar ratio of naphthalene/2-chloropropane of 1:0.8. Yield of isopropylnaphthalene obtained was 54%, with an isomer distribution of 98% β- and 2% α-isopropylnaphthalene.
Reaction SMILES: [C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17]([C:31]5[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=5)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 90 °C
Yield: 73.5 %

Procedure:
A mixture of 250 mg of 25a, 72 mg of pyridine-3-boronic acid, 135 mg of K2CO3 and 5 ml of degassed 90% aqueous DME was heated under N2 for 16 h at 90° C. The reaction was then cooled and diluted with water, and the product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the remainder was chromatographed over silica gel (using a gradient of heptane/ethyl acetate as eluent). The product isolated was triturated with diethylether, to provide 183 mg of 25b; NMR (CDCl3) δ 8.85, 8.56, 7.91, and 7.35 (4×m, 4, pyridyl-H), 8.37 and 6.87 (2×s, 2, Ar—H), 4.45 and 3.40-3.90 (br.m, 4, 2×CH2), 3.05 (bm, 2, CH2), 2.60 (br.m, 2, CH2), 1.90 and 1.70 (2×br.m, 4, 2×CH2), 1.58 (s, 9, tertC4H9).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14]1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[C:18](/[C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)\[C:19]#[N:20])=[CH:3][CH:2]=1
Reactant: N#CCc1ccsc1
Reactant: O=Cc1ccnc2ccccc12
Product: N#C/C(=C\c1ccnc2ccccc12)c1ccsc1
Yield: 30.9 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 3-thiopheneacetonitrile (123 mg) through Method B (production step 3), to thereby yield the target product (yield: 81 mg, 31%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@@H:11]2[NH:16][CH2:15][CH2:14][N:13]([C:17]3[C:26]4[CH:25]=[C:24]([CH3:27])[S:23][C:22]=4[NH:21][C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[N:18]=3)[CH2:12]2)=[CH:5][CH:4]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@@H:11]2[N:16]([CH3:36])[CH2:15][CH2:14][N:13]([C:17]3[C:26]4[CH:25]=[C:24]([CH3:27])[S:23][C:22]=4[NH:21][C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[N:18]=3)[CH2:12]2)=[CH:5][CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(C(F)(F)F)cc2)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
Combine 10-((S)-3-[2-(4-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (325.3 mg, 0.69 mmol), formaldehyde (61.7 μL, 0.76 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (219.8 mg, 1.04 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 298.1 mg (89%) of the title compound as a tan foam: mp 72°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]([OH:22])(=[S:21])[CH3:20].CN(C)C=O>C(OCC)C>[C:19]([S:21][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)(=[O:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SC1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Mixture of tert-butyl 3-iodoazetidine-1-carboxylate (STEP B, 2.05 g, 7.24 mmol), cesium carbonate (4.72 g, 14.5 mmol), thioacetic acid (1.10 g, 14.5 mmol) and dimethyl formamide (10 mL) was stirred at 70° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with diethyl ether (200 mL). The resulting mixture was washed with water (80 mL×3) and brine (50 mL), then dried over magnesium sulfate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:23]([O:30][C:31]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 74 h
Yield: 495.6 %

Procedure:
t-Butyl 4-piperidinyloxyacetate (521 mg, 2.42 mmol) and triethylamine (0.40 ml, 2.9 mmol) were dissolved in methylene chloride (20 ml) and benzyloxycarbonyl chloride (0.41 mmol, 2.9 mmol) was added. The mixture was stirred at room temperature for 74 hours. A saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give 710 mg of t-butyl [N-benzyloxycarbonyl-4-piperidinyloxy]acetate as a colorless oil (84%). Methylene chloride (30 ml) and trifluoroacetic acid (10 ml) were added to this oil (692 mg, 1.99 mmol) and the mixture was stirred at room temperature for 17 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give 555 mg of [N-benzyloxycarbonyl-4-piperidinyloxy]acetate as a colorless solid (96%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:27])[NH:19][C:18]([CH2:28][CH3:29])=[C:17]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35]1([O:41][CH2:42][CH:43]2[O:45][CH2:44]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO>[CH2:28]([C:18]1[NH:19][C:20]([CH3:27])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]([C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:44][CH:43]([OH:45])[CH2:42][O:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:29]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCOC(=O)C1=C(C)NC(CC)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(CC)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCC(O)COc1ccccc1
Yield: 20.1 %

Procedure:
In 46 ml of methanol were dissolved 4.62 g of diethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2-ethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate and 1.46 g of glycidyl phenyl ether, and the solution formed was refluxed under heating for 15 hours. After cooling the reaction solution, the solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chloroform-methanol (95:5 v/v). Crude crystals were recrystallized from ethanol to give 1.22 g of diethyl 2-ethyl-4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:18])[CH2:17][C:15](=O)[CH2:14][C:12](=[O:13])[CH2:11]1>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14]1[C:12](=[O:13])[CH2:11][C:10]([CH3:18])([CH3:9])[CH2:17][CH:15]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: Nc1ccccc1Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC=C(Nc2ccccc2Cl)C(=O)C1

Procedure:
A mixture of 12.75 parts of 2-chloroaniline and 14 parts of dimedone is dissolved in 40 volume parts of ethanol under warming, followed by the addition of 3 drops of glacial acetic acid. The solution is refluxed in a water bath for 2 hours, after which time the ethanol is distilled off and the resulting residue is allowed to cool, whereupon yellow crystals separate. These crystals are collected by filtration, washed with ispropyl ether and recrystallized from acetone. The procedure yields 3-(2-chloroanilino-5,5-dimethyl-2-cyclohexen-1-one as colorless prisms melting at 150°-152°C. Elementary analysis: C14H16NOCL Calcd. C, 67.32; H, 6.45; N, 5.60 Found C, 67.13; H, 6.31; N, 5.82 (b) A mixture of 40 parts of dimedone and 36.4 parts of 2-chloroaniline is heated at 170°-175°C for 45 minutes followed by cooling. The resulting reaction product is recrystallized to obtain yellow cubes. The crystals are collected by filtration, washed well with isopropyl ether and recrystallized from acetone. The procedure yields colorless prisms of 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one. Melting point: 150°-152°C. By procedures similar to those described in Example 1-(a) and (b), the following compounds are produced.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]=[CH:3]1>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (5.2 g, 19.6 mmol) in DCM (80 mL) was added 10% Pd/C (0.5 g) and the suspention was stirred under a H2 atmosphere at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo, then the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/4) to give the product as brown oil (3.1 g, 59.0%).