Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[S:38][N:37]=1.O>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:39]3[S:38][N:37]=[C:36]([CH3:35])[CH:40]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ns1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (10 mg, 0.02 mmol), 3-methyl-5-(tributylstannyl)isothiazole (23.25 mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium(0) (23.07 mg, 0.02 mmol) in toluene (3 mL) was heated to 120° C. for 45 min under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. After removal of solvent, the resulting crude material was reconstituted in DMF and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (55-80% gradient, 0.035% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×50 mL), dried over anhydrous Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to give the title compound. [M+H] calc'd for C26H34FN5O6S, 564. found, 564.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1>[OH-].[NH4+].O.[OH-].[Rh+3].[OH-].[OH-].[OH-].[OH-].[Pd+2]>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ncccc1O
Agent: [Pd+2]
Agent: [Rh+3]
Agent: [NH4+]
Solvent: O
Product: O=C(O)[C@@H]1NCCC[C@@H]1O
Yield: 93.2 %

Procedure:
A mixture of 3-hydroxy picolinic acid (20 g, 0.14 mol), 10% rhodium hydroxide on carbon (The catalyst was prepared according to the literature procedure: William M. Pealman, Tetrahedron Letters, 1967, 8, 1663-1664) (13.2 g), 20% palladium hydroxide on carbon (4.0 g) in 30% ammonium hydroxide solution (40 mL) and water (280 mL) were stirred under hydrogen at 75 psi for 6 days. The catalysts were removed by filtration and the filtrate was concentrated to yield the crude product 77A as a white foam (18.93 g): MS (ES): m/z 146 [M+1]+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][C:13]([C:19]3[C:24]([F:25])=[CH:23][C:22]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:21][C:20]=3[F:30])=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:31][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[F:25][C:24]1[CH:23]=[C:22]([C:26]([OH:29])([CH3:27])[CH3:28])[CH:21]=[C:20]([F:30])[C:19]=1[C:13]1[S:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:31])[CH3:2])=[CH:9][CH:8]=2)=[C:15]([C:16]([NH2:18])=[O:17])[CH:14]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2-[(4-acetylphenyl)amino]-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (50 mg, 0.116 mmol) was taken up in THF (1 mL) and cooled to 0° C. Methylmagnesium chloride (0.136 mL, 0.407 mmol) was added and stirring continued at 0° C. for 2.5 hours. After this time, additional THF (1 mL) was added to aid solubility, the mixture was allowed to warm to room temperature and stirring continued for 2.5 hours. Saturated NH4Cl was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (0-10% MeOH—CHCl3) followed by MPLC (12-100% EtAOc-hexanes) gave 5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(1-hydroxy-1-methylethyl)phenyl]amino}thiophene-3-carboxamide as a brown solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].[CH:10]([C:13]1[O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=2[N:14]=1)=[CH:11][CH3:12].C(Cl)(=O)/C=C/C.NC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[O:19]=[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:15]=1[NH:14][C:13](=[O:18])[CH:10]=[CH:11][CH3:12])[CH2:2][C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)=[O:3]
Reactant: CC(=O)Nc1nccs1
Reactant: CC=Cc1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: C/C=C/C(=O)Cl
Agent: Nc1c(C(=O)O)cccc1C(F)(F)F
Product: CC=CC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 70.6 %

Procedure:
Using the procedure of Step A of Example 1, 19.44 g of 2-acetylamino thiazole and 17.3 g of 2-(1-propenyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one [prepared by Step A of Example 12 of European Pat. No. 40,573 from crotonyl chloride and 2-amino-trifluoromethyl benzoic acid] were reacted to obtain 19.03 g of β-oxo-2-[(1-oxo-2-butenyl)-amino]-N-(2-thiazolyl)-3-trifluoromethyl-benzene-proponamide melting at 206°-208° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[N:59]=[CH:58][CH:57]=[CH:56][N:55]=1.[CH3:60][O:61][C:62]([C:64]1[C:65]([S:70][CH2:71][C:72]2[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=2)=[N:66][S:67][C:68]=1[NH2:69])=[O:63]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:60][O:61][C:62]([C:64]1[C:65]([S:70][CH2:71][C:72]2[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=2)=[N:66][S:67][C:68]=1[NH:69][C:54]1[N:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[O:63]
Reactant: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1N
Reactant: Brc1ncccn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ncccn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
racemic 2,2′-Bis(diphenyl-phosphino)-1,1′-binaphthyl (87 mg, 0.14 mmol) is dissolved in toluene (4.5 mL) and then Tris(dibenzylideneacetone)-dipalladium (0) (44 mg, 0.05 mmol), Cesium carbonate (468 mg, 1.43 mmol), 2-bromopyrimidine (228 mg, 1.43 mmol), and compound 20 (300 mg, 0.96 mmol) are added. The reaction mixture is vigorously stirred at 100° C. for 4 hrs. The reaction is then filtered hot and washed with methylene chloride followed by hot dichloroethane (30 mL). The mother liquor is then concentrated in vacuo and triturated with MeOH to obtain a crude solid which is recrystalized from dichloroethane to provide 21 (265 mg, 71%). 1H NMR (d6 DMSO): δ 10.72 (1H, s), 8.79 (2H, d, J=5.0 Hz), 7.44 (2H, d, J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz), 7.23 (1H, dd, J=5.0, 5.0 Hz), 4.35 (2H, s), 3.86 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][O:22][CH2:23][C@H](O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[O-].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:15])[CH2:21][O:22][CH3:23])[CH:11]=1)[C:5]([OH:7])=[O:6].[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COC(=O)c1cc(O)cc(OC(=O)c2ccccc2)c1
Agent: C[O-]
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate (1.0 eq.), (R)-1-methoxy-2-propanol (1.25 eq.) and triphenylphosphine (1.25 eq.) were suspended in toluene (10 vol). Diisopropyl azodicarboxylate (1.25 eq.) was added at a batch temperature of between 0 and 5° C. over ˜2 h. The mixture was allowed to warm to room temperature and was stirred for further 30 min at this temperature. The resulting suspension was filtered to remove the bulk of the triphenylphosphine oxide formed and the filter cake was washed with toluene (1.5 vol). To the combined toluene fractions containing the resulting methyl 3-[(1S)-2-methoxy-1-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate was added sodium methylate (0.8 eq.) at a batch temperature of between 20 and 30° C. and the mixture was stirred to 1 h. The solution of the resulting methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]-benzoate was then extracted twice with KOH 0.25 M (3.5 vol each) at a batch temperature of between 0 and 5° C. KOH was then added (1 eq.) to hydrolyse the ester moiety and the batch was stiffed for 1 h at a temperature of between 20 and 30° C. The pH of the aqueous phase is then adjusted to 1.5 using conc. hydrochloric at a batch temperature of <30° C. Crude 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid was subsequently extracted into MTBE (2×3 vol) before activated charcoal was added. The batch was stirred for 10 minutes and then filtered. The batch was reduced to 3 pot volumes by distillation at a batch temperature of <45° C. Toluene (4 vol) and heptane (1 vol) were added and vacuum distillation was continued at a batch temperature of <50° C. until no further MTBE was collected. The batch was cooled to a temperature of <40° C., seeded and further cooled to a batch temperature of between 28 and 32° C. The resulting suspension was stirred for 1 h at this temperature before being further cooled to 5 to 10° C. After 2 h stirring at 5 to 10° C. the batch was filtered and washed with cold toluene (1 vol.). Drying at <60° C. furnished 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid in >99% purity as colourless solid with a melting point of 95° C. in a typical yield between 65 and 70% from methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C:38]1[CH:39]=[C:40]([CH:44]([C:51]#[C:52][CH3:53])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]=[CH:42][CH:43]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O>C1COCC1>[OH:36][CH2:37][C:38]1[CH:39]=[C:40]([CH:44]([C:51]#[C:52][CH3:53])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]=[CH:42][CH:43]=1
Reactant: CC#CC(CC(=O)OCC)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(CC(=O)OCC)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution (5.0 mL) of tetrabutylammonium fluoride in THF was added to a solution of ethyl 3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)hex-4-ynoate in THF (10 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (181 mg) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[N:23]1([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:30][CH:31]=2)[CH2:7][CH2:6]1
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1)c1ccc(N2CCOCC2)nc1
Yield: 26.9 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 6-morpholin-4-ylnicotinic acid (81 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol) to give title compound (43.6 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[C:16]([OH:25])=[O:15])[CH:8]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1cccc(-c2ccccc2)c1
Product: O=C(O)c1cccc(COc2cccc(-c3ccccc3)c2)c1

Procedure:
3-(Biphenyl-3-yloxymethyl)-benzoic acid was prepared using general procedure A from 3-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 76 mg. Mass spectrum (ES) MH+=305.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:24]=[CH:23][C:13]([C:14]([NH:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)=[O:15])=[C:12]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[N:11]=1)#[N:3].[C:35]([O:39][C:40]([NH:42][CH2:43][CH2:44][CH2:45][C:46](O)=[O:47])=[O:41])([CH3:38])([CH3:37])[CH3:36].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:24]=[CH:23][C:13]([C:14]([NH:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:46](=[O:47])[CH2:45][CH2:44][CH2:43][NH:42][C:40](=[O:41])[O:39][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:15])=[C:12]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[N:11]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: N#Cc1ccccc1-c1ccc(C(=O)NCC2CCCN2)c(NCCc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC(=O)N1CCCC1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N-(pyrrolidin-2-ylmethyl)nicotinamide hydrochloride (95 mg, 0.2 mmol), 4-(tert-butoxycarbonylamino)butanoic acid (61 mg, 0.3 mmol), HOBT (41 mg, 0.3 mmol), and HBTU (114 mg, 0.3 mmol) were added DMF (1.0 mL) and DIEA (0.1 mL, 0.6 mmol). The reaction mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete. The reaction mixture was then filtered and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and water to give tert-butyl 4-(2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (81.2 mg, 65%). LRMS (M+H+) m/z 629.2.
Reaction SMILES: [CH2:1]([C:8]#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][NH:11][CH2:12][CH2:13][NH2:14].C(=S)=S>C(OCC)(=O)C>[CH3:10][N:11]1[CH2:12][CH2:13][N:14]=[C:8]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC#N
Reactant: CNCCN
Solvent: S=C=S
Solvent: CCOC(C)=O
Product: CCCCCCCC1=NCCN1C
Temperature: 125 °C
Yield: 95.4 %

Procedure:
14.207 g (113.46 mmoles) of heptyl cyanide, 10.726 g (144.69 mmoles) of N-methylethylenediamine and 0.5 ml of carbon disulfide were mixed and heated at 125° C. for 24 hours. The solution was cooled, diluted with ethyl acetate and extracted with dilute hydrochloric acid. The acidic solution was basified with sodium hydroxide and extracted with ethyl acetate. The organic extracts were treated with charcoal, filtered, concentrated and Kugelrohr distilled at 105° C./1 2mm to give 19.73 g (77.3%) of the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].CS[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][N:19]=1>>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][N:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: CSc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1
Reactant: CCCN(CCCCN)c1ccccn1
Product: CCCN(CCCCNc1ncc(Cc2ccc(F)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (1.24 g) and 2-methylthio-5-(4-fluorobenzyl)pyrimid-4-one (1.25 g) were fused together on an oil bath at 160° C. for 2.5 hr. On cooling the residue was crystallised twice from ethanol/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]5-(4-fluorobenzyl)pyrimid-4-one 1.25H2O, 0.56 g (26.%) mp indeterminate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])=[CH:21][CH:20]=1.O>CCOCC>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:24][CH:23]=2)=[O:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a suspension of 83 (135 mg, 0.59 mmol) in ether (10 mL) was added HCl (1.17 mL, 1.00 M, 1.17 mmol) in ether. The mixture was stirred for 3 h and the solvent was removed under vacuo. A suspension of this HCl salt in NMP (3 mL) was added N-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl)benzamide (209 mg, 0.70 mmol). The mixture was stirred at 150° C. for 3 h. After cooling to room temperature, H2O was added. The resulting product precipitate and the solid was filtered, washed with H2O and MeOH, and dried under vacuum to provide 378 (210 mg, 73% yield) as pale solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:25]([O:34]C(OC(C)(C)C)=O)[C:24]([C:42]([F:45])([F:44])[F:43])=[CH:23][CH:22]=1>>[C:30]([O:29][C:27]([C:26]1[C:25]([OH:34])=[C:24]([C:42]([F:43])([F:44])[F:45])[CH:23]=[CH:22][C:21]=1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)Cc1cc(C)c(-c2ccc(O)cc2)s1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: Cc1cc(CC(=O)O)sc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1
Yield: 13 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl [5-(4-hydroxyphenyl)-4-methyl-2-thienyl]acetate (133 mg, 0.51 mmol) obtained in Example (96-4) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (254 mg, 0.56 mmol) obtained in Example (28-5), the title compound was obtained as a pale yellow crystal (35 mg, three-step total yield: 13%).
Reaction SMILES: [CH2:1]([CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]O.[OH-].[K+]>>[CH2:1]1[CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[O:19][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCCC/C=C/CCCCCCCCO
Agent: O=C1CCCCC/C=C\CCCCCCCCO1
Agent: [K+]
Agent: [OH-]
Product: O=C1CCCCCC=CCCCCCCCCO1
Temperature: 180 °C

Procedure:
Alternatively, the ester may be saponified to obtain the ambrettolic acid. The crude ambrettolic acid obtained by saponification was transformed into its glycerine polyester by heating under a slight vacuum at 180° C. for a period of 4 to 5 hours. The resulting polyesters were then depolymerized in the presence of a mineral base, potassium hydroxide, to give ambrettolide which was distilled off by azeotropic distillation using glycerine. After fractionation, 43 g of cis-oxacyclopheptadec-12-en-2-one (Product II) containing 86% of the cis-derivative and 13% of the trans-derivative, was obtained (as determined by GLC analysis) (Tb 125° C.-128° C. at 0.2 mm Hg).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[S:22](N)([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:24])=[O:23].CN([N+]1C=CC=CC=1)C.C(N(CC)CC)C>C(#N)C>[C:29]([O:28][C:26](=[O:27])[NH:25][S:22]([NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)(=[O:24])=[O:23])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NS(N)(=O)=O
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: CN(C)[n+]1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.09 g, 0.33 mmol) and dimethylamino pyridinium N-tert butoxycarbonyl sulfamide (0.12 g, 0.36 mmol) were dissolved in acetonitrile (2.0 mL). After addition of triethylamine (0.05 mL, 0.36 mmol) the reaction mixture was heated to reflux for 16 h. The solvent was removed and the residue subjected to column chromatography (silica gel, heptane/ethyl acetate=9:1/4:1/1:1). The title compound was obtained as a yellow solid (15 mg; 10%); MS: m/e=455.7 (M+H+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C:27](=O)[C:26]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:19])[CH3:18].[BH4-].[Na+]>CO.O.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[C:26]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:25]1=2)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)c2ccc(Cl)cc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (3.2 g, 13.1 mmol) followed by titanium isopropoxide (5.0 mL) to 8-Chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (3.5 g, 11.9 mmol) and stir at room temperature overnight. Dilute the mixture with 20 mL of Methanol and add sodium borohydride (23.8 mmol). Stir the suspension at room temperature for 1 h then dilute with water (200 mL) and ethyl acetate (200 mL). Filter the resulting emulsion through celite and wash with ethyl acetate (3×100 mL). Separate the organics and dry over sodium sulfate. Remove the solvent under vacuum and chromatograph the product over silica gel using ethyl acetate/hexane (5-30%) to elute. This affords the title compound (5.7 g, 93%) as an off white solid: MS (ES+): 523 (M+H).