Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[OH:25][C:26]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([CH3:36])[C:26]=4[OH:25])[CH2:31]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1nc(-c2cccc(C(F)(F)F)c2)nc2ccccc12
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(C(F)(F)F)c3)nc3ccccc13)C2
Yield: 14 %

Procedure:
Reaction of 2-(3-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 56 (14% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.82 and 3.06 (2t, 2H), 3.61 and 4.25 (2t, 2H), 4.48 and 5.11 (2s, 2H), 6.34 and 6.83 (2d, 1H), 6.90 and 7.09 (2d, 1H), 7.63-7.71 (m, 2H), 7.79-7.81 (m, 1H), 7.98-8.09 (m, 2H), 8.25-8.30 (m, 1H), 8.88-8.97 (m, 2H); MS (ESI) m/z 464 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Cl.Cl[CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(SCCN)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
A mixture of 3-methoxybenzenethiol (5 g), 2-chloroethylamine hydrochloride (1.1 eq.) and Cs2CO3 (2.2 eq.) in CH3CN (60 mL) was stirred at 60° C. for 20 h. To the reaction mixture, EtOAc (100 mL) was added, and washed with H2O (2×30 mL). The organic phase was concentrated under reduced pressure to give product 20 (Yield: 6.2 g, 95%), which appeared to be pure by TLC and NMR and was used for the next step reaction without further purification.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[O:9]=[C:7]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)O
Product: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OCc1ccccc1
Yield: 56 %

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-phenylphenyl) propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 56% (purification by flash chromatography, eluent: ether/petroleum ether 6/4) m.p. 79° C. IR (nujol): 3280, 1740, 1690, 1640, 1620 cm-1 1H NMR (CDCl3 /TMS): 7.75 (s, 1H); 7.65 to 7.20 (m, 14H); 7.05 (t, 1H, J=5 Hz); 5.0 (s, 2H); 4.15 (s, 2H); 3.65 (q. app., 2H, J app.=6 Hz); 2.65 (t, 2H, J=6Hz); 2.30 (s, 3H). Microanalysis: C28H27O4NS Calc. % C=71.01 H=5.75 N=2.96 Found. % C=71.08 H=5.60 N=2.46
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1I.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])#[CH:20]>CN(C)C=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:20]#[C:19][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(C#Cc2ccccc2F)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.2 ml, 1.43 mmol) was added to a suspension of 1-Chloro-2-iodo-4-nitro-benzene 69 (Step 1) (100 mg, 0.354 mmol), 1-ethynyl-2-fluorobenzene (100 mg, 0.832 mmol), copper iodide (100 mg, 0.525 mmol), Pd(PPh3)2Cl2 (100 mg, 0.142 mmol) in dimethylformamide (2 ml) at room temperature, then stirred at 70° C. for 2 hours. Reaction was cooled to room temperature and extracted with ether (50 ml), washed with water (20 ml), dried (MgSO4), filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 20% v/v MeCl2/hexanes yielding title product 70 as pale yellow solid (80 mg, 82%).
Reaction SMILES: [C:1](=[O:14])([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:2][CH:3](Cl)[CH3:4].[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O-:28])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16].[K+].[I-].[Na+]>CN(C=O)C>[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O:28][CH:3]([O:2][C:1]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH3:4])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(Cl)OC(=O)OCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 168 h

Procedure:
1-Chloroethyl benzyl carbonate (prepared according to Synthesis 1986, 627), (2.36 g, 11.0 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 20 mmol) and sodium iodide (0.15 g, 1 mmol) in dry DMF (50 ml). After stirring at 50° C. for 7 hours and at room temperature for 7 days the solvent was removed at reduced pressure. The residue was dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After treatment with magnesium sulfate the solution was evaporated to dryness. Yield: 6.8 g. Purity by HPLC: 97% 1H-NMR(DMSO-d6): delta=1.64 (CHCH3); 1.66(N(CH3)COCH3); 2.05 (NCOCH3); 5.23 (CH2); 7.00 (CH); 7.30-7.45 (arom.); 10.12 ppm (NH).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl[C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([NH:2][C:28](=[O:33])[C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice water cooled solution of methyl [trans-4-(5-aminopyridin-2-yl)cyclohexyl]acetate hydrochloride, prepared as above, (831 mg, 2.59 mmol) in DCM (50 mL) was added triethylamine (1.3 mL, 9.31 mmol) followed by methyl chlorooxoacetate (0.31 mL, 3.36 mmol) and the reaction mixture was allowed to stir at O—C for 2 hrs. The reaction mixture was diluted with DCM (100 mL) and washed with water (80 mL) then brine (80 mL) and the aqueous layer was re extracted with DCM (50 mL). The organic washings were combined, dried and concentrated to give the title compound, 865 mg (2.59 mmol, 100%) which was taken through to the next stage; 1H NMR (CDCl3) δ 1.13-1.27 (m, 1H), 1.57-1.64 (m, 3H), 1.84-2.00 (m, 5H), 2.26 (d, 2H), 2.62-2.70 (m, 1H), 3.68 (s, 3H), 3.98 (s, 3H), 7.18 (d, 1H), 8.13 (d, 1H), 8.60 (s, 1H), 8.82 (brs, 1H); MS m/e MH+ 335.
Reaction SMILES: Br[CH:2](Br)[CH2:3][C:4]12[CH2:17][CH:8]3[CH2:9][C:10]([CH2:13][CH:14](Br)Br)([CH2:12][C:6]([C:18]45[CH2:27][C:22]6([CH2:28][CH:29](Br)Br)[CH2:23][CH:24]([CH2:26][C:20]([CH2:32][CH:33](Br)Br)([CH2:21]6)[CH2:19]4)[CH2:25]5)([CH2:7]3)[CH2:5]1)[CH2:11]2.CC(C)([O-])C.[K+].O>CS(C)=O>[C:28]([C:22]12[CH2:23][CH:24]3[CH2:26][C:20]([C:32]#[CH:33])([CH2:19][C:18]([C:6]45[CH2:5][C:4]6([C:3]#[CH:2])[CH2:17][CH:8]([CH2:9][C:10]([C:13]#[CH:14])([CH2:11]6)[CH2:12]4)[CH2:7]5)([CH2:25]3)[CH2:27]1)[CH2:21]2)#[CH:29]
Reactant: BrC(Br)CC12CC3CC(CC(Br)Br)(C1)CC(C14CC5CC(CC(Br)Br)(CC(CC(Br)Br)(C5)C1)C4)(C3)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CC12CC3CC(C#C)(C1)CC(C14CC5CC(C#C)(CC(C#C)(C5)C1)C4)(C3)C2
Reaction time: 48 h

Procedure:
The obtained 3,3′,5,5′-tetrakis(dibromoethyl)-1,1′-biadamantane was dissolved in 200 ml of dimethyl sulfoxide, and then 28 g (250 mmol) of potassium tert-butoxide was added at room temperature and the mixture was stirred for 48 hours. The reaction mixture was added to 400 ml of water, the mixture was extracted 3 times using 200 ml of dichloromethane each time and then washed with 200 ml of water and dried over magnesium sulfate, and the organic layer was concentrated to obtain 11.0 g of 3,3′,5,5′-tetraethynyl-1,1′-biadamantane.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]#[N:19].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.C[O-].[Na+]>C(O)C>[NH2:19][C:18]1[C:3]2[C:4]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[C:5]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]3=[N:7][C:2]=2[S:1][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1c(S)nc2c(c1-c1cccs1)CCCCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CCCCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-mercapto-4-thien-2-yl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonitrile (143 mg, 0.5 mmol), tert-butyl bromoacetate (97 mg, 0.5 mmol) and triethyl amine (51 mg, 0.5 mmol) in ethanol (20 mL) was stirred at room temperature overnight, followed by the addition of NaOMe (30 mg, 0.56 mmol). The mixture was then refluxed for 30 min., and poured onto ice. The precipitate is filtered and washed with water to furnish pure t-butyl 3-amino-4-thiophen-2-yl-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-2-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].C(N(CC)CC)C.[SH2:20]>N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])(=[S:20])[NH2:2]
Reactant: N#Cc1cccc2c1CCC2=O
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1cccc2c1CCC2=O
Reaction time: 16 h

Procedure:
A solution of 12.1 g (77 mmol) of 4-cyano-2,3-dihydro-1H-inden-1-one [see Coll. Czechoslov. Chem. Commun. 4, 3227 (1978)] in 220 ml of pyridine and 10.6 ml (77 mmol) of triethylamine is saturated with hydrogen sulfide for 3 hours at 40° and is then stirred at the same temperature for 16 hours. The reaction mixture is cooled and then concentrated to dryness by evaporation, and 300 ml of water are added to the residue. The yellow product that has crystallized out is filtered off with suction, washed with water, dried and recrystallized from ethyl acetate. In that manner there is obtained the title compound, m.p. 197° (decomp.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[O:9])=[CH:3][CH:2]=1.CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>C1(C)C=CC=CC=1>[CH3:20][N:23]([CH3:25])/[CH:24]=[C:7](\[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)/[C:8]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14])=[O:9]
Reactant: N#Cc1cccc(C(=O)Cc2ccncc2)c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=C(/C(=O)c1cccc(C#N)c1)c1ccncc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-(Pyridin-4-yl-acetyl)-benzonitrile (4.91 g, 22.1 mmol) was dissolved into dry toluene (0.2 ml) and dimethoxymethyl-dimethyl-amine (10.6 g, 88.5 mmol) was added. The reaction mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The solvent was removed under vacuum and crude 3-((E)-3-Dimethylamino-2-pyridin-4-yl-acryloyl)benzonitrile was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)N3CCCCC3)cc2C1

Procedure:
8.1 g (0.025 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin, 2.5 ml (0.025 mole) of piperidine, 11 g (0.025 mole) of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 5.3 ml of triethylamine in 250 ml of dimethylformamide were mixed at ambient temperature for 6 hours. The solvent was evaporated off, the residue was taken up in water, it was extracted with ethyl acetate, the organic phase was washed with a saturated NaHCO3 solution, filtered over celite and washed with a dilute solution of acetic acid and with water. It was dried and the solvent was evaporated off under reduced pressure. The product was purified by crystallization from a 1:1 ethyl/hexane mixture. The product of the heading was obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:42])[N:15]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]1[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]C2CCCCO2)[N:20]=1)[CH3:3].O.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:42])[N:15]([C:16]1[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[N:20]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)N(c1ccccc1)c1nnn(CCCCCCCCOC2CCCCO2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(c1ccccc1)c1nnn(CCCCCCCCO)n1
Reaction time: 46 h

Procedure:
To a stirred, room temperature solution of (±)N'-[2,6-bis(1-methylethyl)phenyl-N-phenyl-N-[2-[8-[(tetrahydro-2H-pyran-2-yl)oxy]octyl]-2H-tetrazol-5-yl]-urea (2.1600 g, 0.0037449 mol) in methanol (20 mL) was added dropwise water (1.0 mL) and 4-methylbenzenesulfonic acid monohydrate (0.0594 g, 0.000312 mol), and the mixture was stirred. After 46 hours the mixture was rotoevaporated, and the residue was chromatographed on silica gel (230 g, 230-400 mesh) using PET ether-diethyl ether (1:2, 15×200 mL) as eluent. Fractions containing product were rotoevaporated from dichloromethane to an oil. The oil was dried in vacuo (95° C., 15 min; 17h, 25° C.) to give the title compound, yield 1.482 g (80%). 1H NMR (CDCl3): δ 9.2 (br s, 1H), 7.5 (t, 2H), 7.4 (m, 3H), 7.3 (d, 1H), 7.2 (d, 2H), 4.5 (t, 2H), 3.6 (t, 2H), 3.2 (septet, 2H), 2.0 (m, 2H), 1.5 (m, 4H), 1.3 (m, 6H), 1.2 (d, 12H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:17][CH:18]1CCOC(=O)CCCCCCCOCC1>>[CH3:1][CH:2]1[CH2:16][CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:18][CH2:17][O:5][CH2:4][CH2:3]1
Reactant: CC1CCOCCCCCCCC(=O)OCC1
Reactant: CC1CCOCCCCCCC(=O)OCC1
Product: CC1CCOCCCCCCCCC(=O)OCC1

Procedure:
Odor: Musk, animalic, warm-powdery, flowery, slightly after saffron.--IR (film): n=1734 cm-1 (νC=O), 1118/1151 cm-1 (νasO--C--C), 1250 cm-1 (νasC--C(=O)--O), 1357 cm-1 (δCH3), 1061 cm-1 (νasC--O--C).--1H-NMR (CDCl3): δ=0.91 (d, J=6.4 Hz, 3H, 13-Me), 1.31-1.66 (m, 15H, 3-H2 -8-H2, 12-H2, 14-Hb), 1.83 (ddt, J=19.1, 9.6 and 5.0 Hz, 1H, 14-Ha), 1.93 (mc, 1H, 13-H), 2.33 (dd, J=6.9 and 6.2 Hz, 2H, 2-H2), 3.34-3.52 (m, 4H, 9-,11-H2), 4.14 (ddd, J=11.0, 5.5 and 5.0 Hz, 1H, 15-Hb), 4.21 (ddd, J=11.0, 10.0 and 4.0 Hz, 1H, 15-Ha).--13C-NMR (CDCl3): δ=18.22 (q, 13-Me), 24.67/25.26 (t, C-3,-7), 25.53 (d, C-13), 27.21/27.40/27.52 (t, C-4,-5,-6), 28.68 (t, C-8), 34.67 (t, C-2), 35.49 (t, C-14), 37.01 (t, C-12), 61.74 (t, C-15), 67.67/70.16 (t, C-9,-11), 173.93 (s, C-1).--MS (El): m/z (%)=55 (100) [C4H7⊕ ], 83 (64) [C6H11⊕ ], 99 (30) [C6H11O⊕ ], 138 (25) [M⊕ --C6H14O2 ], 155 (23) [M⊕ --C6H13O], 213 (2) [M⊕--C2H3O], 227 (2) [M⊕ --CHO], 256 (1) [M⊕ ].--C15H28O3 (256,39): calculated C 70.27, H 11.01; found C 70.26, H 11.09.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OC)[CH:9]=2)=[O:4].[NH2:27][C@H:28]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31].CCN(CC)CC>CO>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][C@H:28]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Reactant: COC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 150 °C

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (20 mg, 0.06 mmol), (2R,3R)-methyl 3-amino-2-hydroxy-4-phenylbutanoate (43 mg, 0.13 mmol) and Et3N (0.04 mL, 0.27 mmol) in MeOH (2 mL) was heated at 150° C. in a microwave for 3 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 7 mg. MS: (−) m/z 496.34 (M-1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=3)[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:28][C:29]([C:32]([F:35])([F:33])[F:34])=[N:30][N:31]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1

Procedure:
The title compound was prepared according to Procedure A from 4-benzyloxyaniline and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.69(1H, bs), 9.53(1H, s), 8.91 (1H, s), 8.65(1H, dd), 8.11 (1H, d), 7.64(2H, d), 7.45(5H, m), 7.15(2H, d), 5.19(2H, s); m/z (M+1+) 464.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CS(C)=O>CN(C)C=O>[O:31]1[CH2:32][CH2:33][N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=4)[S:11][CH:12]=3)=[CH:4][C:3]=2[N+:25]([O-:27])=[O:26])[CH2:29][CH2:30]1
Reactant: CCOc1ccc(-c2nc(-c3ccc(Cl)c([N+](=O)[O-])c3)cs2)cc1OCC
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccc(N4CCOCC4)c([N+](=O)[O-])c3)cs2)cc1OCC
Yield: 91.5 %

Procedure:
A solution of 1 g of 4-(4-chloro-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole and 636 mg of morpholine dissolved in 20 ml of dimethylformamide and 20 ml of dimethyl sulfoxide was refluxed at 150° C. for 2-3.5 hours with heating. The reaction mixture was subjected to vacuum distillation. The residue was added to ice water, and an aqueous sodium hydrogencarbonate solution was added. The solution was extracted with dichloromethane three times. The combined extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-n-hexane to obtain 1.03 g of 4-(4-morpholino-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.S(Cl)([Cl:24])=O>ClCCl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([Cl:24])=[O:21])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Yield: 99.2 %

Procedure:
A slurry of [4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-acetic acid (19, Chart B) (24.0 g, 85.4 mmol) in dichloromethane (300 ml) was treated with thionyl chloride (12.4 ml, 170 mmol). After heating at reflux temperature for 3.5 hours, the solvent and excess reagent were removed by evaporation to yield sufficiently pure product (25.4 g, 99%).
Reaction SMILES: [CH:1](=[C:8]1[CH:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[CH:1](=[C:8]1[CH:16]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCCC1
Reactant: O=C1C(=Cc2ccccc2)C(Br)c2ccccc21
Solvent: c1ccccc1
Product: O=C1C(=Cc2ccccc2)C(NC2CCCCCC2)c2ccccc21
Reaction time: 24 h
Yield: 81.8 %

Procedure:
2-Benzylidene-3-bromoindan-1-one 2 (299 mg, 1 mmol) was dissolved in benzene (10 mL). Cycloheptylamine (255 μL, 2 mmol) was added and reaction mixture was stirred for 24 h. Solvent was removed in vacuum and 5 (271 mg, 82%) was isolated as yellow crystals by column chromatography (Hexanes/EtOAc 9:1) followed by crystallization from dichloromethane with pentane.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12](Br)[C:13]#[CH:14]>>[CH2:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: Nc1cccc(C(F)(F)F)c1
Product: C#CCNc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A mixture of 3-trifluoromethylaniline (30 g) and propargyl bromide (12 g) was stirred at 80° C. for 3 hours, followed by filtration of the reaction mixture. The filtrate was subjected to column chromatography to give N-propargyl-3-trifluoromethylaniline (7 g). A solution of N-propargyl-3-trifluoromethylaniline thus obtained (5.1 g) and ethoxycarbonyl isothiocyalate (3.7 g) in tetrahydrofuran (100 ml) was stirred at room temperature for 8 hours, and the solvent was removed under reduced pressure. The concentrated residue was extracted with chloroform (200 ml), washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 5.7 g of 2-ethoxycarbonlimino-3 (3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (i)).
Reaction SMILES: C[O:2][CH:3]([O:10]C)[C@@H:4]1[O:9][CH2:8][CH2:7][C@H:5]1[OH:6].[H][H]>O>[OH:6][C@@H:5]1[CH2:7][CH2:8][O:9][C@H:4]1[CH:3]([OH:10])[OH:2]
Reactant: [H][H]
Reactant: COC(OC)[C@@H]1OCC[C@H]1O
Solvent: O
Product: OC(O)[C@@H]1OCC[C@H]1O
Temperature: 95 °C
Yield: 14.4 %

Procedure:
A mixture of 9.25 g of product from Example 172, 15 ml of water and 1.5 g of DOWEX-50W-X8(100-200 mesh, hydrogen form) is heated at 95° C. for 4 hours. The reaction mixture is cooled to room temperature, filtered and the residue washed with water. The filtrate is treated with toluene and concentrated in vacuo to give 1.1 g of the desired product as a stickyyellow oil.