Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC[O-].[Na+].Cl[CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32])=[O:24]>CCO>[C:1]([NH:4][C:5]([CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32])=[O:24])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: Cc1ccc(O)c(C(=O)CCCl)c1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCC(=O)c1cc(C)ccc1O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
Diethyl acetamidomalonate (12.84 g, 59.11 mmol) was added to freshly prepared 0.29 M NaOEt (225 ml) in EtOH at 0° C. The solution resulting after brief sonication was transferred to an addition funnel and added over six minutes to a suspension of 20 (10.68 g, 53.74 mmol) in EtOH (50 ml) at 0° C. After stirring the reaction mixture for 18 hours at room temperature, solvent was removed in vacuo. Cold 0.25 N HCl (200 ml) was added and the aqueous phase was extracted with CHCl3 (200 ml, 2×100 ml). The organic layer was washed with H2O (100 ml). After solvent removal, the solid was purified by silica gel flash column chromatography using 4% acetone/-CH2Cl2 to furnish 18.1 g (89%) of diethyl (acetylamino)[3-(2-hydroxy-5-methylphenyl)-3-oxopropyl]propanedioate (I) as a solid: NMR δ 1.26 (t, 6H, J=7), 2.04 (s, 3H), 2.30 (s, 3H), 2.78 (t, 2H, J=7), 2.98 (t, 2H, J=7), 4.17-4.34 (m, 4H), 6.79 (s, 1H), 6.88 (d, 1H, J=8), 7.25-7.30 (m, 1H), 7.47 (s, 1H), 11.97 (s, 1H). Anal. calcd. for C19H25NO7 : C 60.15, H 6.64, N 3.69. Found: C 60.23, H 6.73, N 3.77.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][CH2:23][C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:22][CH2:23][C:24](=[O:28])[N:25]([CH3:26])[CH3:27]
Reactant: CN(C)C(=O)CCCSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)CCCSc1c(Cl)ccc2c1CCNCC2
Yield: 57 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-(3-dimethylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in DCM (1 mL) at ambient temperature and add 4M hydrogen chloride in dioxane (200 μL, 0.8 mmol). Continue stirring until TLC shows consumption of starting material. Concentrate in vacuo, triturate the obtained solid with dry diethyl ether and dry at 50° C. under high vacuum overnight to give the title compound as a hygroscopic white solid (45.0 mg, 57%). MS (ES+) m/z: 327 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CC#N>[N:11]1([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Product: N#Cc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of 4-cyanobenzylbromide (1.0 g, 5.1 mmol) in MeCN (10 ml) was added morpholine (0.44 g, 0.44 ml, 5.1 mmol) and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and partioned between CH2Cl2 and NaOH (2M). The organic layer was separated, dried over MgSO4 and dried to give the desired nitrile (0.70 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Br:15][C:16]1[N:17]=[CH:18][C:19]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:14][CH2:13]3)=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:20][CH:21]=1
Reactant: Brc1ccc(I)cn1
Reactant: COC(=O)c1cc(C2CC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cc(C2CC2)ccc1Nc1ccc(Br)nc1

Procedure:
Obtained (0.155 g, 43% of yield) following the procedure described in Intermediate 15 starting with methyl 2-amino-5-cyclopropylbenzoate (described in Intermediate 8 (step A)) (1.05 mmol, 0.200 g), 2-bromo-5-iodopyridine (1.05 mmol, 0.297 g) and Cs2CO3 (2.09 mmol, 0.682 g) instead of NaOtBu.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:20]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: Brc1cccnc1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3cccnc3)[C@@H]2C1
Yield: 61 %

Procedure:
The product of Example 52D (230 mg, 1.0 mmol) and 3-bromopyridine were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, CH2Cl2:methanol, 95:5, Rf. 0.3) to provide the title compound (190 mg, 61% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.24 (dd, J=12.6, 4.1 Hz, 1H), 3.30 (m, 1H), 3.40 (m, 1H), 3.64 (dd, J=7.8, 3.4 Hz, 1H), 3.92-4.08 (m, 3H), 4.70 (m, 1H), 5.10 (m, 2H), 6.90 (m, 1H), 7.24 (m, 3H), 7.35 (m, 2H), 7.73 (d, J=2.7 Hz, 1H), 7.86 (d, J=4.7 Hz, 1H); MS (DCI/NH3) m/z 310 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])CCC.[CH2:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24](Cl)(=[O:26])=[O:25])[CH2:14][CH2:13]1>O1CCCC1.CCCCCC>[CH2:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:26])=[O:25])[CH2:16][CH2:17]1
Reactant: O=S(=O)(Cl)c1ccccc1C1CCCCC1
Reactant: O=C1CCCN1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCCN1S(=O)(=O)c1ccccc1C1CCCCC1
Yield: 42.2 %

Procedure:
The operation is carried out as in Example 12, using 1.97 g of 2-pyrrolidinone in 100 cm3 of tetrahydrofuran, 15.5 cm3 of a 1.5M solution of n-butyllithium in hexane, and 6 g of (4-cyclohexyl)benzene-sulphonyl chloride [J. Am. Chem. Soc. 62, 513 (1940)] in 24 cm3 of tetrahydrofuran. 3 g of expected product is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][C:10](C(OCC)=O)([C:13]([O:15][C:16](C)(C)[CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OC(C)(C)C)CCc2cc([N+](=O)[O-])cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCc2cc([N+](=O)[O-])cnc21
Temperature: 35 °C
Reaction time: 3 h

Procedure:
A mixture of 7-tert-butyl 7-ethyl 3-nitro-5,6-dihydro-7H-cyclopenta[b]pyridine-7,7-dicarboxylate (6.2 g, 18.4 mmol) in 30 mL of TFA and 30 mL DCM was stirred at 35° C. for 3 hours then concentrated to dryness. The residue was dissolved in 200 mL of EtOAc and washed with saturated NaHCO3 (2×25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]=1.ClC1C=CC=CC=1Cl>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Brc1ccccc1C1=NCCc2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1nccc2ccccc12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A mixture of 28.6 g (100 mmol) of 1-(2-bromophenyl)-3,4-dihydroisoquinoline, 86.9 g (1 mol) of manganese dioxide and 200 ml of 1,2-dichlorobenzene was stirred at 180° C. for 5 h. After cooling, the mixture was diluted with 500 ml of toluene and filtered through silica gel. After the solvent had been removed, the product was obtained as a yellow oil. The yield at a purity of approx. 99.0% was 26.0 g (91 mmol), 91.4% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:8][C:9]=1[NH:10]C(=O)C(F)(F)F)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2([OH:23])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C2(O)CCOCC2)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1sc(C2(O)CCOCC2)cc1N

Procedure:
5-(4-Hydroxytetrahydropyran-4-yl)-3-(2,2,2-trifluoroacetylanino)thiophene-2-carboxylic acid methyl ester and potassium carbonate were reacted by method GA. The product with the molecular weight of 257.31 (C11H15NO4S) was obtained in this way; MS (ESI): 258 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]2[CH:23]=[C:24]([Cl:30])[C:25]([Cl:29])=[C:26]([Cl:28])[CH:27]=2)[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([NH:1][C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])=[N:3]1)#[N:10]
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(NC(=O)C2CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in CH2Cl2 at 0° C., were added TEA (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=4[F:32])[CH:18]=3)[CH:13]=[CH:12][N:11]=2)[NH:7][CH:6]=1)=[O:4].[OH-].[Na+].O.Cl>C1COCC1>[F:32][C:26]1[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=1[NH:24][C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:8]2[NH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[CH:15]=1)=[O:33]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Temperature: 70 °C

Procedure:
To a stirred solution of 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid methyl ester (140 mg, 0.31 mmol) in THF (8 ml) was added 5M NaOH solution (1 ml, 5 mmol). The mixture was heated at 70° C. for 3 hours, cooled to room temp, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates were filtered, washed with water, and dried to give 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid as white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][P:10]([CH2:14][NH:15]C(OC(C)(C)C)=O)(=[O:13])[O:11][CH3:12])=O)(C)(C)C.[ClH:23]>>[ClH:23].[NH2:8][CH2:9][P:10]([CH2:14][NH2:15])(=[O:13])[O:11][CH3:12]
Reactant: COP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Agent: Cl
Product: COP(=O)(CN)CN

Procedure:
The tert-butoxycarbonyl protective group of the methyl phosphinate 17 (2.470 g; 7.31 mmol) is removed using 3N. methanolic hydrochloric acid (50 ml ), by analogy with Example 4. The methyl phosphinate hydrochloride 18 is obtained (1.522 g, 99% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCCCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 82.9 %

Procedure:
Beginning with 0.01 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.01 mL (0.057 mMol) octanoyl chloride, 0.013 gm (83%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.Cl>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A 500 mL Parr hydrogenation vessel was charged with 12.36 g (55.9 mmol) of (E)-3-(4-nitrophenyl)-2-propenoic acid, ethyl ester, 100 mL of absolute ethanol, 15 mL of concentrated hydrochloric acid and 0.75 g of 10% palladium-on-activated charcoal. The slurry was purged with nitrogen and then agitated under an initial pressure of 44.5 psi of hydrogen gas. After 16 h, 18.5 psi had been consumed. The flask was evacuated, purged again with nitrogen and the contents filtered through Celite and evaporated. The residue was dissolved in water and adjusted to pH 9 with solid sodium carbonate. The resulting mixture was extracted thrice with dichloromethane, and the combined organic extracts dried over Na2SO4, filtered and evaporated to provide 9.31 g, 86% of title compound as a yellow oil, sufficiently pure for use in subsequent reactions.
Reaction SMILES: [C:1]1(Br)[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3].C([Li:17])CCC>>[C:1]1([Li:17])[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3]
Reactant: [Li]CCCC
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Product: [Li]c1c(F)c(F)c(F)c(F)c1F

Procedure:
The reaction mixture may also be reacted directly without isolation of the C6F5Br with butyl lithium to produce C6F5Li which,in turn, is reacted with BCl3 or BF3 to produce (C6 F5)3B.
Reaction SMILES: [N+:1]([CH2:4][C@@:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[CH:8][CH2:9]2)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][CH2:4][C@@:5]1([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[CH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC=C[C@@H]21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@]1(CN)C[C@@H]2CC=C[C@@H]21
Reaction time: 4.5 h

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.98 g, 7.41 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (2.07 g, 37.0 mmol) and ammonium chloride (392.7 mg, 7.41 mmol) were added, and the mixture was stirred for 4.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow solid (1.99 g, this compound was used directly in the next reaction without being purified).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[CH2:27][CH2:26][CH2:25][C:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]4)[CH2:13]3)[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1.[CH3:30][Zn]C.C(O)(C(F)(F)F)=O>C1COCC1.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:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[CH2:27][CH2:26][CH2:25][C:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:15]4)[CH2:13]3)[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1
Reactant: CC(C)(C)CN1CC2(CCCC(Cn3cnc4c(Br)cc(C#N)cc43)C2)OC1=O
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cc2c1ncn2CC1CCCC2(C1)CN(CC(C)(C)C)C(=O)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
4-bromo-1-((3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.100 g, 0.218 mmol) was dissolved in THF (1.00 mL) and treated with tetrakis(triphenylphosphine)palladium(0) (0.503 g, 0.044 mmol) followed by dimethylzinc (1.09 mL, 2.18 mmol). Addition of the dimethylzinc resulted in an exotherm with gas evolution and a color change from brownish-yellow to bright yellow. The reaction mixture was purged with nitrogen and capped. The reaction was allowed to stir at rt for 18 h. The reaction mixture turned dark brown over the course of the reaction. The reaction was quenched with sat. aq. ammonium chloride solution and diluted with EtOAc. The layers were separated, and the organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 15 min run; 50 mL/min elution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 35-69% solvent A) to afford the title compound (0.035 g, 31% yield) as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br. s., 1H), 8.19 (s, 1H), 7.44 (s, 1H), 4.21 (d, J=7.03 Hz, 2H), 3.31 (dd, J=8.78, 18.57 Hz, 2H), 2.85 (s, 2H), 2.56 (s, 3H), 2.06-2.21 (m, 1H), 1.81 (d, J=11.04 Hz, 1H), 1.73 (d, J=13.80 Hz, 1H), 1.40-1.58 (m, 4H), 1.25-1.35 (m, 1H), 0.95-1.08 (m, 1H), 0.83 (s, 9H). MS (m/z) 395.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (31.8 g) in toluene (100 mL) was added ethylene glycol (36.5 mL) and p-toluenesulfonic acid monohydrate (0.426 g). The two phase mixture was stirred rapidly at ambient temperature for 72 hours. The reaction was diluted with water (900 mL) and extracted with ether (900 mL). The organic layer was washed with saturated sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. After filtration, the title compound was obtained by concentration under high vacuum.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=[O:13].C1CCN2C(=NCCC2)CC1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:13][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc2ccccc2c1)OCc1ccccc1
Yield: 100.5 %

Procedure:
To a stirred solution of 2-naphthylacetic acid (1 g, 5.4 mmol) in acetonitrile (10 mL) were added DBU (0.97 mL, 6.4 mmol) and benzyl bromide (0.77 mL, 6.4 mmol). After 3 hours the mixture was concentrated, and the residue was taken up in ethyl acetate. The organic phase was washed with 10% citric acid, 10% NaHCO3 and brine, dried (MgSO4), and concentrated to give 2-naphthylacetic acid benzyl ester as a white solid (1.5 g, 100%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][F:17])[N:11]=1)(=O)=O.[CH3:18][NH2:19]>>[F:17][CH2:16][C:12]1[N:11]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][NH:19][CH3:18])[CH:15]=[CH:14][CH:13]=1
Reactant: CN
Reactant: CS(=O)(=O)OCCC#Cc1cccc(CF)n1
Product: CNCCC#Cc1cccc(CF)n1
Yield: 15 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(C), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 11 mmol) and N-methylamine 40% in aqueous solution (20 mL). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to 90/10 with 1% TEA as eluent) to afford 324 mg of 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine as a pale oil (Yield: 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.C1(C)C=CC=CC=1.[CH3:29][N:30]=[C:31]=[O:32]>C(N(CC)CC)C>[CH3:29][NH:30][C:31]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1)=[O:32]
Reactant: Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Yield: 80 %

Procedure:
31 parts of 5-(4'-amino-2'-trifluoromethylphenoxy)-benzisothiazole, 400 parts of toluene, 1 part of triethylamine and 11.4 parts of methyl isocyanate were stirred for 12 hours at 80° C., after which the solvent was removed under reduced pressure and the residue was purified over silica gel, using chloroform as the mobile phase. 29.4 parts (80% of theory) of 5-(4'-methylaminocarbonylamino-2'-trifluoromethylphenoxy)-benzisothiazole of melting point 138° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[N:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:28]3[CH2:29][CH2:30][CH:25]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:26][CH2:27]3)[S:8][C:6]=2[N:7]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: Clc1nc(N2CCOCC2)c2cc(CN3CCC(N4CCCCC4)CC3)sc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde was reacted with 4-piperidinopiperidine using the general reductive amination General Procedure to yield 1′-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-[1,4]bipiperidinyl, which was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester in General Procedure A. Purification on silica yielded 390. NMR: (CDCl3): 1.45-1.48 (2H, m), 1.52-1.56 (6H, m), 1.79-1.81 (2H, m), 2.02-2.05 (2H, m), 2.25-2.27 (1H, m), 2.53-2.56 (4H, m), (3.06 (2H, d), 3.72 (2H, s), 3.86-3.90 (4H, m), 3.95-3.99 (4H, m), 5.25 (2H, s, br.), 7.10 (1H, s), 9.30 (1H, s). MS ESI m/z 495 (MH+, 100%)