Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]=[N+]=[N-])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].NC[C@@H]1OC(=O)N(C2C=CC(N3C=C(C)N=N3)=C(F)C=2)C1>>[Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH2:27])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH:14]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Agent: Cc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)nn1
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)cn1
Yield: 102.6 %

Procedure:
(5R)-3-{4-[4-(tert-Butyl(dimethyl)silyloxymethyl)-1H-imidazol-1-yl]-3-fluorophenyl}-5-(azidomethyl)oxazolidin-2-one (WO 9928317, WO 9910343, WO 9731917) (2.0 g, 4.17 mmol) was reacted as described for Intermediate 16 to give the title compound (1.8 g) as a solid, which was taken to the next step without further purification.
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([OH:5])=[O:4]>C(O)CCC>[ClH:1].[ClH:1].[CH2:13]([O:4][C:3]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:5])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1

Procedure:
Prepared from 1-(4-carboxymethyloxyphenyl)-4-[2-(piperidin-4-yl)ethyl]piperazine dihydrochloride and n-butanol.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[O:15])[N:6]([CH2:8][C@H:9]([C@H:12]([OH:14])[CH3:13])[CH2:10][OH:11])[CH:7]=1.[C:17](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:26]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[CH:28][CH:27]=1)[C:18]1[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([C:17]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[CH:24][CH:25]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH2:10][C@H:9]([CH2:8][N:6]2[CH:7]=[C:2]([CH3:1])[C:3](=[O:16])[NH:4][C:5]2=[O:15])[C@H:12]([OH:14])[CH3:13])=[CH:33][CH:32]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn(C[C@@H](CO)[C@@H](C)O)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H](Cn2cc(C)c(=O)[nH]c2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
To a stirred solution of 33 (0.6 g. 2.6 mmol) in 20 ml of anhydrous pyridine was added 0.9 g (2.66 mmol) of DMTCl. After being stirred at room temperature for 5 hrs the reaction was quenched with methanol (3 ml), concentrated and portioned between 10% citric acid and ethyl acetate. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a solid foam. The crude product was chromatographed on silica eluting with ethyl acetate to afford 0.95 g (69%) of 34 as an amorphous white solid. 1H NMR (DMSO-d6): δ 11.16 (s, 1H), 7.28 (m, 6H), 7.21 (m, 4H), 6.85 (m, 4H), 4.59 (d, J=5 Hz, 1H), 3.76 (m, 2H), 3.74 (s, 6H), 3.57 (m, 1H), 3.10 (m, 1H), 2.95 (m, 1H), 2.11 (m, 1H), 1.67 (s, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:11])=[O:10])[CH:6]=[CH:5]C=CC=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.[H-].[Na+].[O:34](CCCCBr)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[O:34]([CH2:5][CH2:6][CH2:1][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:9]1(=[O:10])=[O:11])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1Cc1ccccc1
Reactant: BrCCCCOc1ccccc1
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccccc1
Yield: 67 %

Procedure:
The synthesis was carried out analogous to the preparation of 83.1 using 82 (0.23 g, 1.25 mmol), NaH (0.030 g, 1.25 mmol) and 4-phenoxy-butyl bromide (0.115 g, 0.5 mmol) in DMF (5 mL). Purification by flash column chromatography on silica gel gave 83.2 (0.1 g, 67% yield) as a white solid (m p 92-94° C.).
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:15]C(=O)N(C)C)[CH:14]=1)[C:9]([NH2:11])=[O:10])=O.[OH-].[Na+]>>[SH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([SH:15])[CH:14]=1)[C:9]([NH2:11])=[O:10]
Reactant: CN(C)C(=O)Sc1cc(SC(=O)N(C)C)cc(C(N)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cc(S)cc(S)c1

Procedure:
3,5-Bis(dimethylcarbamoylthio)benzamide was subjected to hydrolysis with aqueous sodium hydroxide according to the ordinary procedure, giving 3,5-dimercaptobenzamide.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[C:7]([CH:18]=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20](=[O:24])([O:22][CH3:23])[NH2:21].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9](=[O:10])[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:7]([CH:6]=1)[CH2:18][NH:21][C:20](=[O:24])[O:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1C=O
Reactant: COC(N)=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1CNC(=O)OC
Temperature: 130 °C
Yield: 69.9 %

Procedure:
A 25-mL microwave vial equipped with a magnetic stirrer was charged with 102a (1.00 g, 3.83 mmol), methyl carbamate (575 mg, 7.66 mmol), trifluoroacetic acid (871 mg, 7.66 mmol), triethylsilane (888 mg, 7.66 mmol) and acetonitrile (10 mL). The vial was loaded in a Biotage microwave and heated at 130° C. for 1.5 h. After this time, the solution was concentrated in vacuo. The resulting residue was partitioned between methylene chloride (100 mL) and a saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with methylene chloride (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 60% ethyl acetate/hexanes) to afford a 71% yield (858 mg) of 102b as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 7.29 (m, 1H), 7.12 (d, 1H, J=7.7 Hz), 5.60 (br s, 1H), 4.27 (br s, 2H), 3.65 (s, 3H), 3.57 (q, 2H, J=6.8 Hz), 3.20 (q, 2H, J=6.7 Hz), 1.31 (s, 9H), 1.26 (t, 3H, J=6.7 Hz), 1.09 (t, 3H, J=6.8 Hz); MS (ESI+) m/z 321.2 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[F:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23].O>CN(C)C=O>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH:14]2[CH2:15][CH2:16][CH2:17][CH:13]2[F:12])[CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1F
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1F
Reaction time: 0.67 h

Procedure:
A suspension of sodium hydride (0.3; 60% oil dispersion) in dimethylformamide (5 mL) is treated with 4-amino-3,5-dichloropyridine (0.62 g) and the mixture is stirred for 40 minutes. A solution of 3-(2-fluoro-cyclopentyloxy)-4-methoxybenzoyl chloride in dimethylformamide (12 mL) is added, and the mixture is stirred at 80-90° C. for 1 day. The solution is cooled, poured into water (75 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1:3 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-(2-fluorocyclopentyloxy)-4-methoxybenzamide (0.26 g), m.p. 167-169° C. [Elemental analysis: C,53.8; H,4.2; N,6.75; Cl,17.8%; calculated: C,54.15; H,4.3; N,7.0; Cl,17.8%].
Reaction SMILES: CC(O)C.[NH2:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[C@@H:14]([NH:21][C@H](C3C=CC=CC=3)C)[CH2:13]2)[C:7]=1[F:30].O.[F-].[K+].[H][H]>[OH-].[OH-].[Pd+2].O>[NH2:21][C@@H:14]1[CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][N:12]([C:8]2[C:7]([F:30])=[C:6]([NH2:5])[N:11]=[CH:10][N:9]=2)[CH2:13]1
Reactant: C[C@H](N[C@H]1CN(c2ncnc(N)c2F)CCC1C(=O)O)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ncnc(N2CCC(C(=O)O)[C@@H](N)C2)c1F
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a 10 L reaction were charged under N2, i-PrOH (3.5 L), H2O (3.5 L), 3-7 (1.0 equiv, 0.97 mol, 350 g), potassium fluoride mono hydrate (290 g, 3.0 eq, 3.0 mol) and 35 g of 20% Pd(OH)2/C (10% v/w). After evacuated/refilled with hydrogen three times, the mixture was warmed to 40-50° C. and vigorously stirred at that temperature under 1 atmosphere of hydrogen. After 18 hours, LC/MS indicated <1% of starting material 3-7 remained. The mixture was purged with N2 for 20 min, cooled to 22° C., and filtered. Both the wet cake and filtrate contained the product and processed separately.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1
Solvent: CCO
Product: Nc1cccc(-c2ccccc2)c1
Yield: 99.4 %

Procedure:
A 2-1atmospheric hydrogenation reactor was charged with 250 g (1.26 mol) of m-nitrobiphenyl, 12.5 q of 5% Pd-Cl, and 1250 ml of ethanol. A theoretical amount of hydrogen gas was absorbed at room temperature. The catalyst was removed by filtration and the filtrate was distilled of the solvent, obtaining 212 g of m-aminobiphenyl (yield 99.9%). Another batch of reaction was effected on the same scale except that 254 g (1.28 mol) of m-nitrobiphenyl was used, obtaining 215 g of m-aminobiphenyl (yield 99.7%),
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8](O)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[ClH:4].[C:8]([Cl:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalic chloride (800 μL) is added dropwise to a solution of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoic acid, hydrochloride (2.33 g) in dichloromethane (20 mL) containing one drop of N,N-dimethylformamide. The mixture is stirred for two hours at room temperature and concentrated under reduced pressure. Cyclohexane is added and evaporated under reduced pressure to afford 2.55 g of 4-[3-(cis and trans-3,5-dimethylpiperidino)propoxy]benzoyl chloride, hydrochloride used without further purification.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11](O)=[O:12])[CH3:7].C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])[CH3:7]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CCOC(=O)CC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
tert-butanol (2.8 mL, 37.8 mmol) was added to a stirred solution of malonic acid monoethyl ester (5 g, 37.8 mmol) in acetonitrile (45 mL). DCC (8.58 g, 41.6 mmol) dissolved in acetonitrile (5 mL) was added dropwise with stirring over a period of 2 hours. The reaction mixture was filtered and the filtrate was concentrated to afford 4.72 g (66%) of malonic acid tert-butyl ester ethyl ester. LCMS: 189.11 (M+1)+ 93.4%, 1H NMR: (CDCl3): δ 4.2 (q, 2H), 3.3 (s, 2H), 1.4 (s, 9H), 1.3 (t, 3H).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[C:19]1[CH2:24][CH2:23][CH:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]#[N:35])[CH:32]=3)[NH:27][CH:26]=2)[CH2:21][CH2:20]1>>[C:34]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:22]1[CH2:21][CH2:20][CH:19]([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[C:17]=3[N:16]=[CH:15][CH:14]=[CH:13]4)[CH2:2][CH2:3]2)[CH2:24][CH2:23]1)#[N:35]
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Reactant: c1cnc2c(N3CCCNCC3)cccc2c1
Product: N#Cc1ccc2[nH]cc(C3CCC(N4CCCN(c5cccc6cccnc56)CC4)CC3)c2c1
Yield: 92 %

Procedure:
The title compound was prepared according to Example 3, Step 4 except that 8-[1,4]diazepan-1-yl-quinoline was used instead of 1-(2-methoxy-phenyl)-[1,4]diazepane and 3-(4-oxo-cyclohexyl)-1H-indole-5-carbonitrile was used in place of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone. Yield: 92%; MS (ES) m/z (relative intensity): 450 (M++H, 100).
Reaction SMILES: [NH3:1].Cl[C:3]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4]1=[O:13].O>ClCCl>[NH2:1][C:3]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: N
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O
Product: CCOc1ncccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
104 ml (728 mmol) of a 7N methanolic ammonia solution were added dropwise to a cooled solution of 47 g (145 mmol) of 3,5-dichloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 250 ml of dichloromethane under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature overnight. 250 ml of water and 250 ml of dichloromethane were added to the reaction mixture. After stirring for 5 min, a white solid was precipitated and filtered off and washed with water and dichloromethane. Drying in a vacuum drying oven resulted in 26 g of the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[O:36][C:35]([CH3:38])([CH3:37])[CH:34]=[CH:33][C:16]2=[C:17]2[C:26]=1[C:25](=[O:27])[C:24]1[C:19](=[CH:20][CH:21]=[C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]3=1)[N:18]2[CH3:32].Cl>ClCCl>[C:1]([C:34]1[C:35]([CH3:37])([CH3:38])[O:36][C:15]2[C:16](=[C:17]3[C:26](=[C:13]([O:12][CH3:11])[CH:14]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]4=2)[N:18]3[CH3:32])[CH:33]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C=CC(C)(C)O2
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)C1=Cc2c(cc(OC)c3c(=O)c4c5ccccc5ccc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.81 mmol of butyryl chloride and 0.673 mmol of AlCl3 in 2 ml of anhydrous dichloromethane is added, in small portions, to 0.135 mmol of the product of Example 3 in 2 ml of dichloromethane at 0° C. The reaction mixture is stirred for 4 hours at ambient temperature and then poured into a 10% HCl solution. After conventional treatment of the organic phases and evaporation thereof under reduced pressure, chromatography of the residue over silica gel (dichloromethane/methanol) allows the expected product to be isolated.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13](Br)[CH2:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:14][CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(=O)N1c2cccc3c2C(CCC3Br)C1c1ccccc1
Product: CC(=O)N1c2cccc3c2C(CCC3N2CCCC2)C1c1ccccc1
Yield: 76 %

Procedure:
The compound (500 mg) obtained in Example 187 and pyrrolidine (0.24 ml) were subjected to amination according to the procedure of Example 134 to yield 370 mg (76%) of the titled compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:24]([CH3:25])[CH3:23])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1
Reactant: CNC
Product: CN(C)CCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 19.1, 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and Dimethylamine were converted to yield {5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-dimethyl-amine as light brown semisolid, MS: 338 (MH+).
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1NC(C)(C)N(C)[C:10]1=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C=C)=O.C1CCC=CC=1>CC#N.O.CCOCC>[CH:6]12[CH2:5][CH2:4][CH:3]([CH:8]=[CH:7]1)[CH2:2][C@H:9]2[CH:10]=[O:17]
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: C=CC=O
Agent: Cl
Solvent: CCOCC
Solvent: C1=CCCC=C1
Solvent: O
Product: O=C[C@@H]1CC2C=CC1CC2
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of 5 (32 mg, 0.12 mmol) in CH3CN/H2O (95/5 v/v, 1.0 M) was added acrolein (501 μL, 7.5 mmol), and cyclohexadiene (238 μL, 2.5 mmol). The solution was stirred for 24 h, after which time the reaction mixture was diluted with Et2O (10 mL) and washed with H2O (10 mL). The aqueous layer was extracted with Et2O (10 mL×2) and the combined organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10% ether/pentane) afforded the title compound as a colorless oil in 82% yield (280 mg, 2.06 mmol); 14:1 endo:exo; 94% ee. Product ratios were determined by GLC (Bodman Γ-TA column, 75° C. isotherm, 23 psi) tr=51.0 min and 54.4 min. 1H NMR, 13C NMR, and IR data were consistent with previously reported values (Ishihara et al. (1998), supra).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][N:24]=4)[C:19](=[O:26])[C:18]([C:27](O)=[O:28])=[CH:17]3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].S(Cl)(Cl)=O.[CH:34]([NH2:37])([CH3:36])[CH3:35]>O1CCCC1>[CH:34]([NH:37][C:27]([C:18]1[C:19](=[O:26])[C:20]2[C:25](=[N:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH:11]=2)[CH:17]=1)=[O:28])([CH3:36])[CH3:35]
Reactant: CCOc1cccc(-c2cccc(-n3cc(C(=O)O)c(=O)c4cccnc43)c2)c1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOc1cccc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro(1,8]naphthyridin-4-one-3-carboxylic acid from Step 2 and thionyl chloride (4 eq) in tetrahydrofuran (10 ml/mmol) was refluxed for 45 minutes, then evaporated. The residue was dissolved in the same volume of tetrahydrofuran, isopropylamine (5 eq) was added and the mixture was stirred at room temperature for 18 hours. After quenching with saturated aqueous ammonium chloride solution, the resulting mixture was partitioned between ethyl acetate and water, and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in methylene chloride to afford the N-Isopropyl-1-[3-(3-ethoxyphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19](=[O:22])[CH:20]=[CH2:21])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[C:41]([NH2:43])[CH:40]=[CH:39][N:38]=2)[O:34][N:33]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](=[O:22])[CH2:20][CH2:21][NH:43][C:41]1[CH:40]=[CH:39][N:38]=[C:37]([C:35]2[O:34][N:33]=[C:32]([C:26]3[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])[CH:36]=2)[CH:42]=1)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Nc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 89 °C
Yield: 43.7 %

Procedure:
(S)-tert-butyl 4-(tert-butoxycarbonylamino)-5-oxohept-6-enoate (0.94 g) and 2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-amine hydrochloride salt (0.40 g) were dissolved in acetonitrile (4 mL). Diisopropylethylamine (0.52 mL) was added and the mixture wad heated at 89° C. for 25 h. The mixture was cooled to room temperature, diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 0.5:99.5 methanol:dichloromethane then 5:95 methanol:dichloromethane to yield (R)-tert-butyl 4-(tert-butoxycarbonylamino)-7-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)-5-oxoheptanoate (316 mg) as a beige foam. 1H NMR (CDCl3): 8.25 (m, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.17 (m, 1H), 6.98 (m, 1H), 6.47 (m, 1H), 5.20 (m, 1H), 5.00 (m, 1H), 4.22 (m, 1H), 3.59 (m, 2H), 2.90 (m, 2H), 2.32 (m, 2H), 2.10 (m, 1H), 1.83 (m, 1H), 1.45 ppm (s, 18H). MW=619 confirmed by LC-MS, tr=13.23 min (Method Y) MH+=617-621.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[C:1](=[O:12])([S:18][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCS
Product: CCCCCCC/C=C/C(=O)SCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-pentanethiol as starting materials to give the aimed compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn2ccc(Oc3cccc(Cl)c3)nc12
Temperature: 70 °C
Yield: 92.7 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in DMF was added 3-chlorophenol (42 mg, 0.331 mmol) and K2CO3 (190 mg, 1.380 mmol). The mixture was heated at 70° C. for several hours. Water was added and the solid formed was isolated by filtration and air dried to yield 70 mg 5-(3-chlorophenoxy)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as an orange solid (93% yield). LCMS (M+1=274)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CC(C)=CCBr
Reactant: COc1ccc(O)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OCC=C(C)C)c(C=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (7.6 g, 50 mmol) in dry N,N-dimethylformamide (100 mL) was added potassium carbonate (10.4 g), followed by 1-bromo-3-methylbut-2-ene (10.0 g, 67 mmol). The mixture was stirred at room temperature for 48 hours and ethyl acetate added. Sufficient 1M hydrochloric acid was cautiously added to neutralize the base, and the organic layer was washed with water three times, followed by brine, and dried over magnesium sulfate. The mixture was filtered, and solvent removed from the filtrate under reduced pressure, to provide 5-methoxy-2-(3 -methylbut-2-enyloxy)benzaldehyde.