Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1.C([OH:28])C.[OH-].[Na+]>O>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:28])=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc(C(F)(F)F)ccc1S2
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(C(F)(F)F)ccc1S2
Temperature: 75 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a mixture of 40 mg of 2-(10,11-dihydro-8-trifluoromethyl-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 1 ml of ethanol was added 200 mg of sodium hydroxide in 1 ml of water, and the mixture was stirred at 75° C. for 5 hours. After cooling, the solvent or ethanol was removed by distillation to obtain a residue, to which was added water, and the resulting mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a yellow oil, which was thin-layer chromatographed and developed with chloroform-methanol (10:1), thereby obtaining 15 mg (yield: 38%) of 2-(10,11-dihydro-8-trifluoromethyl-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.[Cl:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2cnccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc2cnccc2n1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-1,6-naphthyridine (E. M. Hawes, J. Heteroc. Chem. 11(2), 151 (1974)) (3.8 g) in CCl4 (230 mL) were added N-chlorosuccinimide (4.2 g) and benzoylperoxide (320 mg). The mixture was brought to reflux with two 150-watt spotlights and irradiated for 4 hr. The mixture was then cooled to room temperature, evaporated to dryness, and chromatographed on flash silica gel using ethyl acetate:toluene (1:1) as eluant to give the title compound, 80% pure and used as is for the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7](CCS)=[N:6][S:5](=[O:12])(=[O:11])[N:4]=1.Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([NH:21][C:22]([NH2:24])=[NH:23])[S:19][CH:20]=1>>[NH:21]([C:18]1[S:19][CH:20]=[C:16]([CH2:15][S:19][CH2:20][CH2:16][NH:17][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:12])[N:6]=2)[N:17]=1)[C:22]([NH2:24])=[NH:23]
Reactant: N=C(N)Nc1nc(CCl)cs1
Reactant: CNC1=NS(=O)(=O)N=C1CCS
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1

Procedure:
When a solution of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] is reacted with 4-chloromethyl-2-guanidinothiazole hydrochloride and a strong base, the title compound is thereby produced, which is identical to the product obtained in Example 31.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8]([OH:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17]O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][C:8]3([C:11]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:17][O:19]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: OCc1ccccc1C1(O)CCN(CC2CC2)CC1
Agent: Cl
Product: c1ccc2c(c1)COC21CCN(CC2CC2)CC1

Procedure:
Treatment of 1-cyclopropylmethyl-4-hydroxy-4-(α-hydroxy-2-tolyl)piperidine with hydrochloric acid by the method described in Example 16d provides 1'-cyclopropylmethyl-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine] as an oil (hydrochloride salt, m.p. 222°-224°).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C:39]1[N:40]=[C:41]([CH2:44][C:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])[S:42][CH:43]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][N:47]([C:45](=[O:46])[CH2:44][C:41]4[S:42][CH:43]=[C:39]([CH3:38])[N:40]=4)[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1csc(CC(=O)N2CCNCC2)n1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)Cc2nc(C)cs2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-(4-methyl-thiazol-2-yl)-1-piperazin-1-yl-ethanone (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C39H45Cl2N6O3S [(M+H)+] 747.2646, observed 747.2642.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[S:6][CH:7]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:17][OH:18].O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[N:17][OH:18])[S:6][CH:7]=1)#[N:2]
Reactant: N#Cc1csc(C=O)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1csc(C=NO)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
11.6 g (84.6 mmol) of 4-cyanothiophene-2-carbaldehyde were dissolved in 140 ml of methanol and 12.3 g (116.1 mmol) of sodium carbonate were added. 6.5 [lacuna] (93.5 mmol) of hydroxylamine hydrochloride were subsequently added at 15° C. with cooling, a little at a time, and the mixture was stirred for 2 hours at 10° C. After 80 ml of water had been added, the reaction mixture was extracted five times using in each case 50 ml of diethyl ether, the organic phase was dried over sodium sulfate and the solvent was removed in vacuo. 12.5 g of the required product resulted as a yellow crystal powder (96% of theory).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[AlH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1>O>[C:1]([O-:4])(=[O:3])[CH3:2].[AlH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CC(=O)O
Agent: C1CC[AlH]OC1
Solvent: O
Product: CC(=O)[O-]
Temperature: 1100 °C
Reaction time: 1 h

Procedure:
Pseudoboehmite (20.0 g) was slowly added to a vigorously stirring mixture of acetic acid (51.0 mL) in water (200 mL). The resulting slurry was decanted after 10 minutes and then centrifuged at 6000 rpm for 1 hour to yield a clear viscous solution. Removal of the volatiles in vacuo (10−2 Torr) at 90° C. results in clear, white granules. The granules were dissolved in water and dried for 24 hours at 80° C. to yield a clear glassy material. The alumoxane was heated from 25° C. to 225° C. at the rate of 1° C./min., soaked for 30 mins. at 225° C., followed by a temper ramp up to 300° C. at the rate of 2° C./min., and soaked for 80 mins., with a final ramp to the maximum temperature of 1100° C. (over 360 minutes) which was then maintained for 400minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[O:22][CH3:23].[C:24]1([NH2:35])[C:29](F)=[C:28](F)[C:27](F)=[C:26]([NH2:33])C=1F.Cl.Cl>CN(C=O)C.O>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]=[N:33][C:26]4[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=4)=[C:15]([O:20][CH3:21])[CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:7][C:2]=1[N:1]=[N:33][C:26]1[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: COc1cc(-c2ccc(-c3ccc(N)c(OC)c3)o2)ccc1N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc(-c3ccc(N=Nc4ccccn4)c(OC)c3)o2)ccc1N=Nc1ccccn1
Yield: 70 %

Procedure:
2,5-Bis[3-methoxy-4-(2-pyridylimino)aminophenyl]furan (4o, DB746) was prepared according to the procedure for 4f using diamine 3i and S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide as starting materials. Free base: yellow crystalline solid, mp 212-213° C. (DMF/H2O). Yield: 70%. 1H NMR (DMSO-d6): 3.82 (s, 6H), 6.89 (d, 2H), 6.98 (s, 2H), 7.38 (m, 4H), 7.54 (dd, 2H), 7.95 (dd, 2H), 8.32 (d, 2H), 8.62 (d, 2H). Dihydrochloride: yellow solid. 1H NMR (DMSO-d6): 3.97 (s, 6H), 7.36 (s, 2H), 7.47 (d, 2H), 7.62 (d, 4H), 7.85 (dd, 2H), 8.20 (d, 2H), 8.45 (d, 2H), 8.89 (d, 2H), 9.37 (br s, 2H), 10.10 (br s, 2H), 11.86 (br s, 2H). Anal. Calcd. for C30H26N6O.2.0HCl.1.0H2O (609.5): C, H, N, Cl.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 56.7 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 4-chlorophenylboronic acid (0.058 g; 0.37 mmol) in DME-water (1 mL) for 2.5 h. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.056 g (51%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:23]=3)[CH:20]=2)=[C:11]([C:31](O)=[O:32])[CH:10]=[N:9]1>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:12]4[N:8]([CH3:7])[N:9]=[CH:10][C:11]=4[C:31]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:32])=[O:30])=[CH:20][N:19]3[N:21]=2)[CH:25]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1

Procedure:
Using morpholine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (53 mg, 32%). Mp.: 229° C. MS: m/z=433.3 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[C:3]1[O:7][C:6]2[C:8]([O:18]C)=[C:9]3[C:14](=[C:15]([O:16]C)[C:5]=2[CH:4]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[CH3:1][Si:2]([CH3:21])([CH3:20])[C:3]1[O:7][C:6]2[C:8](=[O:18])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COc1c2ccccc2c(OC)c2oc([Si](C)(C)C)cc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)c1cc2c(o1)C(=O)c1ccccc1C2=O
Reaction time: 1 h
Yield: 75 %

Procedure:
To 1.2 gram (4 mmoles) of crude product 2-trimethylsilyl-4,9-dimethoxy-naphtho[2,3-b]furan in 50 mL of acetonitrile/water (4:1) in ice bath, 4.8 grams (8.7 mmoles) of cerium ammonium nitrate (CAN) solution in 50 mL of acetonitrile/water (1:4) was added dropwise over 10 minutes. The mixture was further stirred in ice bath for 1 hour, and then evaporated to remove acetonitrile. The remaining aqueous suspension was filtered, and the collected solid was washed with water and crystallized in ethanol/water. Pure crystal product was filtered and dried under vacuum. 0.89 grams of product (overall yield 75%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 0.41 (s, 9H), 7.16 (s, 1H), 7.75-7.78 (m, 2H), 8.19-8.26 (m, 2H). Mass (M+H) is 271.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].CCOC(C)=O>CN(C=O)C>[C:22]([CH2:21][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccccc1-c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A dispersion of 530 mg of 60% sodium hydride in mineral oil and 10 ml of DMF is treated, dropwise, with a solution of 1.50 g (6.6 mmol) of 5-(2-hydroxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile in 20 ml of DMF. The reaction is stirred 30 min at RT, then cooled in an ice bath and 1.11 g (6.6 mmol) of ethyl bromoacetate in 30 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred overnight under N2. The mixture is concentrated under vacuum, the residue taken up in 80 ml of water and extracted with EtOAc. The aqueous phase is acidified to pH=5 with 10% HCl and extracted with EtOAc (4×80 ml). The combined EtOAc extracts are dried (MgSO4) and the solvent removed to leave an orange solid. This solid is recrystallizedfrom EtOAc to give 740 mg of 5-(2-carboethoxymethoxyphenyl)-6-methyl-2-oxo-1,2 -dihydro-3-pyridinecarbonitrile as a yellow solid, m.p. 188°-190° C. Yield, 37%. 1H-NMR (d6 -DMSO): δ 1.20 (t,3H): 2.18 (s,3H); 4.15 (q,2H); 4.80 (s,2H); 7.0 (q,2H); 7.20 (d,1H); 7.35 (t,1H); 8.00 (s,1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Brc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(Br)cc2)[C@@H]1O
Yield: 40.9 %

Procedure:
The title compound (310 mg, 41%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (400 mg, 1.42 mmol) and 4-bromophenyl-1H-imidazol-2-ylmethylamine (359 mg, 1.42 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1)=[O:14].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:26][N:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[S:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:14]
Reactant: O=S(c1nc2ccccc2[nH]1)c1ccccc1-c1ccccn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(S(=O)c2ccccc2-c2ccccn2)nc2ccccc21
Yield: 75.3 %

Procedure:
2-[2-(2-Pyridyl)-phenyl sulphinyl]-1H-benzimidazole (Example 13) (0.7 g) in dry dimethylformamide (50 ml), methyl iodide (0.34 g) and anhydrous potassium carbonate (1.1 g) were stirred at room temperature for 1.75 hours. The mixture was poured onto water, extracted into ethyl acetate, washed, dried and evaporated under reduced pressure to leave the title compound as a cream solid (0.55 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13](OCC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH2:8].[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Ethyl (2,4-dibenzyloxyphenoxy)acetate (3.9 g) is added in small portions to a stirred suspension of lithium aluminium hydride (0.21 g) in dry tetrahydofuran (100 mL) with ice-cooling. The mixture is allowed to warm to room temperature and stirred for a further 30 minutes. The reaction mixture is cooled in an ice-bath and water is added dropwise. After stirring for 1 hour the mixture is filtered through hyflo and the insolubles washed with tetrahydrofuran. Evaporation of the combined filtrate plus washings and crystallisation of the resulting solid from petroleum ether (bp 40-60° C.) containing a little ethyl acetate gives 2-(2,4-dibenzyloxy-phenoxy)ethanol hemihydrate (1.8 g) as a white solid, m.p. 47-52° C. [Elemental analysis:- C,73.3; H,6.25%. Calculated for C22H22O4.0.5H2O:- C,73.5; H,6.45%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[C:10]([CH3:19])=[N:9]2)=[CH:5][CH:4]=1.Cl.CC[OH:25]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:17]=[C:16]([OH:25])[S:15][CH:14]=3)[C:10]([CH3:19])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(=O)CSC#N)c(C)n2)cc1
Reactant: CCO
Agent: Cl
Product: COc1ccc(Cn2cc(-c3csc(O)n3)c(C)n2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
According to Scheme 2, Step 4: To a solution of 1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-thiocyanatoethanone (6.57 mmol, 1.98 g) in EtOH was added HCl concentrated (1 mL) and the reaction mixture was stirred under reflux for 8 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was diluted with water. The aqueous phase was basified with NaOH and was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was evaporated. The crude residue was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 95:4.5:0.5) as eluent to yield 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-ol (3.42 mmol, 1.03 g, 52%).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].[CH:12]([O:14]CC)=[CH2:13]>>[CH:12]([CH2:13][CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:14]
Reactant: C=C(C)C1CCC(C)(O)C1=C
Reactant: C=COCC
Product: C=C(C)C1CCC(C)=C1CCC=O
Yield: 68.5 %

Procedure:
12 drops of 85% phsophoric acid were added to a mixture, cooled to -15° C in a laboratory autoclave, of 76 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 72 g of ethyl vinyl ether. After gassing with argon, the autoclave was brought, in an oil bath of 180° C, to an internal temperature of 150° C (this took about 15 minutes) and held at this temperature until a distinct drop in pressure occurred (about 100 minutes). The reaction mixture was then quenched, taken up in ether, washed with aqueous bicarbonate solution and water, the solution dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product (110 g), obtained as a yellow oil, was fractionated and yielded 61 g (68%) of pure 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene having a woody, earthy fragrance; boiling point 0.2 = 64°-65° C; nD20 = 1.4888; IRfilm : νmax = 3080, 2725, 1725, 1642, 1440, 1370, 1060 and 895 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH:19]=[CH2:20])[C:9](=[O:11])[CH3:10].CCN(CC)CC.O>CN(C=O)C.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]=[CH:19][C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:8]([C:9](=[O:11])[CH3:10])[CH2:7][C:6]=2[CH:21]=1
Reactant: C=Cc1cc(Cl)ccc1N(Cc1cc(Br)ccc1I)C(C)=O
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2cc(Br)ccc2C=Cc2cc(Cl)ccc21
Temperature: 60 °C
Yield: 44.1 %

Procedure:
To a stirred solution of N-(5-Bromo-2-iodo-benzyl)-N-(4-chloro-2-vinyl-phenyl)-acetamide (0.55 g, 1.5 mmol) and Et3N (0.63 mL, 4.5 mmol) in DMF (25 mL) was added PdCl2 (40 mg, 0.23 mmol) and the reaction was heated to 60° C. When the reaction was complete by HPLC the mixture was poured into H2O and extracted with Et2O. The Et2O layer was washed with H2O (2×20mL) and brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography eluting with CH2Cl2 to give 1-(8-Bromo-2-chloro-6H-dibenzo[b,f]azocin-5-yl)-ethanone (0.24 g, 60%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].P(Br)(Br)([Br:27])=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:27][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:19]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCSc1ccccc1-c1nc(Br)c2ccc(C(F)(F)F)cc2n1
Yield: 25.3 %

Procedure:
A mixture of 500 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one, 615 mg of phosphorus oxybromide and 2 ml of acetonitrile was refluxed for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 149 mg of 4-bromo-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 3).
Reaction SMILES: C1(N[N:8]=[C:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C=CC=CC=1.C([O-])(=O)C.[Na+].[C:23]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C.[Zn]>[CH3:16][C:15]1[C:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NNc1ccccc1)C(C)=O
Reactant: O=C1CCCCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2c(c1C)CCCCC2
Temperature: 80 °C
Yield: 14 %

Procedure:
Ethyl 2,3-dioxobutanoate-2-phenylhydrazone (20.9 g) (T. D; Lash et al., J. Org. Chem. 1992, 57, 4809-4820) in acetic acid (50 ml) was added dropwise to a stirred solution of sodium acetate (10 g), and cycloheptanone (10 g) in acetic acid (100 ml) at 60° C. over 30 minutes. Throughout the addition, small portions of zinc dust (30 g) were added. The reaction was stirred for an additional hour at 80° C., then poured into ice-water (500 g). The resulting solid precipitate was filtered and recrystallised from ethanol to give the product as white needles (2.77 g, 14%), NMR d(CDCl3) 1.38 (3H, t), 1.60-1.95 (6H, m), 2.24 (3H, s), 2.48 (2H, t), 2.68 (2H, t), 4.30 (2H, q), 8.70 (111, bs); M/z (+) 222 (MH+), 176.