Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C([NH:18][C:19]([C:21]2[C:29]3[CH:28]=[C:27]([C:30]4[C:35]([CH3:36])=[CH:34][N:33]=[C:32](Cl)[N:31]=4)[S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])C2C=CC(OC)=CC=2)=CC=1.C(OC([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:36][C:35]1[C:30]([C:27]2[S:26][C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:19]([NH2:18])=[O:20])[C:29]=3[CH:28]=2)=[N:31][C:32]([NH:54][CH2:53][CH2:52][CH2:51][CH:48]2[CH2:49][CH2:50][NH:45][CH2:46][CH2:47]2)=[N:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: COc1ccc(C(NC(=O)c2cccc3sc(-c4nc(Cl)ncc4C)cc23)c2ccc(OC)cc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(N)=O)cccc2s1
Temperature: 97 °C

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid [bis-(4-methoxyphenyl)-methyl]-amide (1.14 g, 2.15 mmol), 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (1.04 g, 4.30 mmol) and diisopropylethylamine (1.12 mL, 6.45 mmol) in 1,4-dioxane (10 mL) is heated at 97° C. under a nitrogen atmosphere for 3 days. After concentration and subsequent chromatography on silica gel, eluting with MeOH in dichloromethane 0-2%, the desired product is obtained as a solid. The solid is suspended in dichloromethane (20 mL), followed by the successive addition of triethylsilane (1.5 mL) and TFA (5 mL). The resultant yellow solution is stirred for 2 hours. After concentration the solid is dissolved with stirring in MeOH (30 mL) and dichloromethane (30 mL) and the solution is treated in portions with 1.0 N LiOH (15 mL) to form a suspension. The suspension is concentrated at 45° C. under atmospheric pressure for 30 minutes, then methanol and dichloromethane are evaporated off in vacuo. The suspension is filtered and the yellow solid is dried under vacuum at 45° C. to provide the title compound (0.890 g, 100% yield). ES+(m/z) 410 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O>[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]2[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=2)[CH2:16][CH2:15]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN2CCC(O)CC2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
In 45 ml of dimethylformamide was dissolved 6.0 g (31.8 mmol) of ethyl 5-chloromethyl-2-furancarboxylate followed by addition of 9.64 g (95.5 mmol) of 4-hydroxypiperidine and the mixture was stirred at room temperature for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with 100 ml of chloroform and washed with saturated aqueous sodium chloride solution twice. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 7.84 g (97.4%) of ethyl 5-(4-hydroxypiperidinomethyl)-2-furancarboxylate (Compound s) as light brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].I[CH3:13]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:13])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
A 250-mL single-necked round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 4-bromo-6-chloropyridazin-3(2H)-one (1.00 g, 4.77 mmol) and DMF (15 mL). Sodium hydride (60% by weight in oil, 229 mg, 5.73 mmol) was added in one portion. After stirring at room temperature for 10 minutes, iodomethane (1.02 g, 7.16 mmol) was added and the reaction stirred at room temperature for 1.5 h. The reaction was then quenched with aqueous saturated sodium bicarbonate (10 mL) and the resulting solution poured into water (150 mL). The mixture was then extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate. The drying agent was then removed by filtration, and the filtrate was concentrated under reduced pressure to residue. Purification by column chromatography afforded 103e in a 68% yield (722 mg) as a white solid: mp 107-108° C.; 1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:13]=[CH:12][O:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:14]1[CH:15]=[C:16](B(O)O)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12>>[N:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:13]=[CH:12][O:11][N:10]=3)[CH:5]=[CH:6][CH:7]=2)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: OB(O)c1cnc2ccccn12
Reactant: Brc1cccc(Nc2ccon2)c1
Product: c1cc(Nc2ccon2)cc(-c2cnc3ccccn23)c1

Procedure:
Prepared using procedure outlined in Procedure H using (3-Bromo-phenyl)-isoxazol-3-yl-amine and imidazo[1,2-a]pyridine-3-ylboronic acid as the coupling partners.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[S:7][C:8]([Cl:17])=[C:9]([Cl:16])[C:10]=1[CH2:11][C:12]([O:14]C)=[O:13])C.[OH-].[Na+]>CO>[C:12]([CH2:11][C:10]1[C:9]([Cl:16])=[C:8]([Cl:17])[S:7][C:6]=1[CH2:5][C:4]([OH:18])=[O:3])([OH:14])=[O:13]
Reactant: CCOC(=O)Cc1sc(Cl)c(Cl)c1CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1sc(Cl)c(Cl)c1CC(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of the product from step c) (1.14 g, 3.66 mmol) in MeOH (7 ml) at 0° C. was treated dropwise with 2M NaOH (3.8 ml). The reaction was warmed to 22° C. and stirred overnight. The solvent was evaporated and the residue was dissolved in 2 M NaOH (50 ml) and extracted with ether (2×50 ml). The basic layer was cooled to 0° C. and acidified to pH 1 with 6 M HCl. The acidic layer was back extracted EtOAc (4×100 ml) and the organic layer was dried (MgSO4) and concentrated. The crude solid was triturated with hexanes and filtered providing 2.75 g (73%) of the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(O)(=O)C>O1CCCC1.[Zn]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: FC(F)(F)c1cnc(Cl)nc1
Temperature: 25 °C

Procedure:
2,4-Dichloro-5-trifluoromethyl-pyrimidine (300 mg, 1.4 mmol), zinc dust (90 mg, 1.4 mmol) and tetrahydrofuran (3 ml) heated to reflux. Acetic acid (0.16 ml, 2.8 mmol) in tetrahydrofuran (3 ml) added dropwise to the mixture over 30 minutes. The resultant mixture was heated for a further 3 hours and then allowed to cool to room temperature and filtered through GF-A paper. The liquors were concentrated and wet with dichloromethane. The mixture was washed with dilute bicarbonate solution and then concentrated in vacuo furnishing a crude material from which the desired target molecule was produced.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=4[O:32][CH3:33])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 84.7 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H- indazole (1.9 g, 8.6 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (2.6 g, 8.6 mmol), K2CO3 (1.2 g), and acetonitrile (75 ml) was refluxed for 6 hours. The reaction was poured into water and a white solid settled from solution. This was collected, dried and afforded 3.2 g of product. The product was recrystallized from ethanol to yield 2.7 g (71%) of 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxyl-3-methoxy-phenyl]ethanone as glistening white flakes, m.p.=158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>>[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([NH:12][C:10]1[S:11][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:22]
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1nc(-c2sc(NC(=O)C(C)(C)C)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and 2,2-dimethyl-propionyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][C:3]=1[O:17][CH3:18].C.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22]>C(OCC)(=O)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:14])([CH3:15])[O:16]2)=[CH:4][C:3]=1[O:17][CH3:18])=[C:21]=[O:22]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Solvent: CCOC(C)=O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N=C=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To 4-amino-3-methoxyphenylboronic acid pinacol ester (24.08 mmol, 6 g) and charcoal (0.29 g) in ethyl acetate (50 ml), was added trichloromethyl chloroformate (48.2 mmol, 5.81 mL) and the mixture was stirred at 70° C. for two hours. After cooling to room temperature the solids were removed by filtration and the filtrate concentrated in vacuo to give 6.7 g of 2-(4-isocyanato-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31])[CH3:21].CCN(C(C)C)C(C)C>>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH3:21]
Reactant: CCOc1ccccc1CCN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1CCNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(2-Ethoxy-phenyl)-ethylamine and DIEA to give 2-[2-(2-ethoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 404 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Al](C)C.C([O:22][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=O)C.O>O1CCOCC1>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:32]([C:34]2[S:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[O:33])[N:26]=1)=[O:22]
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (259 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) at r.t. in dioxane (4 ml) under an argon atmosphere was added trimethylaluminium (0.63 ml; 2 M solution in heptane)-->foaming. The mixture was stirred at r.t. for 2 h. A solution of 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (100 mg) in dioxane (4 ml) was then added. The mixture was heated to 100° C. over night. The mixture was cooled to r.t. and H2O (0.8 ml) was added (-->bubbling). After 15 min stirring, MgSO4 was added and stirring was continued for another 15 min. The mixture was then filtered and the cake was washed with dichloromethane. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide as light yellow solid. 474.1 ([M+H]+)
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.[CH3:13][NH:14][S:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16]>>[NH2:11][C:10]1[C:5]2[S:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]([S:15]([NH:14][CH3:13])(=[O:16])=[O:17])[CH:23]=[CH:22][CH:21]=3)[C:6]=2[N:7]=[C:8]([Cl:12])[N:9]=1
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Nc1nc(Cl)nc2c(Br)csc12
Product: CNS(=O)(=O)c1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Yield: 71.2 %

Procedure:
The target compound (480 mg, 71% yield) was prepared in the same manner as Step 1 of Example 11 using 7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (500 mg, 1.90 mmol) and 3-(N-methylsulfamoyl)phenylboronic acid (409 mg, 1.90 mmol).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.[ClH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][Cl:20])[CH:14]=1>C(O)C>[ClH:20].[ClH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][S:1][C:2]2[NH:6][C:5]3=[CH:7][S:8][CH:9]=[C:4]3[N:3]=2)[CH:14]=1
Reactant: COc1ccnc(CCl)c1
Reactant: Sc1nc2cscc2[nH]1
Agent: Cl
Solvent: CCO
Product: COc1ccnc(CSc2nc3cscc3[nH]2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
1.6 g of 2-mercaptothieno[3,4-d]imidazole and 2 g of 4-methoxypicolyl chloride hydrochloride in 50 ml of ethanol were heated at 60° C. for about one hour and stirred at room temperature for a further 40 hours. After the crystalline substance had been filtered off, it was suspended in acetone, the mixture was stirred at room temperature for one hour, and the crystals were filtered off with suction and dried in air. Colorless crystals, melting point 330° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])[C:5]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[CH3:36][OH:37]>>[CH3:36][O:37][C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])[C:5]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCCC(C)(C)C
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCCC(C)(C)C)nc(-c2ncccn2)nc1OC
Temperature: 105 °C
Reaction time: 4 h

Procedure:
Sodium hydride (60% oil dispersion 354 mg) was cautiously added to a suspension of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide (580 mg) in dry methanol (5 ml) in a 10 mm Wheaton reacti-vial™ and the resulting mixture stirred at 105° C. for 4 hours. The reaction was then partitioned between ethyl acetate (20 ml) and 2N aqueous hydrochloric acid (10 ml) and the organic phase separated. The aqueous was extracted with ethyl acetate (20 ml ) and the organic phases combined, washed (water 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of dichloromethane:methanol 100:0 changing to 98.5:1.5 gave N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide as an off-white coloured solid (189 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.Cl>O1CCOCC1>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[N:3]=[C:4]([OH:19])[C:5]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:23][CH:22]=1
Reactant: Oc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Reactant: NCc1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1nc(NCc2ccc(F)cc2)nc2ccc(-c3ccc(F)cc3)nc12
Yield: 93.3 %

Procedure:
A solution of 2-chloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ol (730 mg) and 4-fluorobenzyl amine (398 mg) in 1,4-dioxane (20 mL) was heated at 80° C. overnight. 1N HCl (5 ml) was added to the mixture and the resulting solid was filtered to provide 0.9 g of 2-(4-fluorobenzylamino)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-ol which was characterized by its mass spectrum as follows: MS (m/z) 365 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([CH2:22][CH2:23][CH3:24])=[CH:20][C:19]3[C:18]([CH3:26])([CH3:25])[CH2:17][CH2:16][C:15]([CH3:28])([CH3:27])[C:14]=3[CH:13]=2)=O)=[CH:6][CH:5]=1.[Br-].[CH3:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N-]=[N+]=[N-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:12][C:21]2[C:22]([CH2:23][CH2:24][CH3:31])=[CH:13][C:14]3[C:15]([CH3:28])([CH3:27])[CH2:16][CH2:17][C:18]([CH3:26])([CH3:25])[C:19]=3[CH:20]=2)=[CH:8][CH:9]=1
Reactant: CCCc1cc2c(cc1C(=O)c1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc2c(cc1C=Cc1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
4-[(3-n-Propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid methyl ester (2.7 mmol) in THF (25 mL) was treated with methyltriphenylphosphonium bromide/sodium azide (1.2 g, 3.1 mmol) and the solution was allowed to stir at ambient temperature for 3 h. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic solution was separated and washed with water and brine, dried (MgSO4), filtered, and concentrated to give a yellow oil. The crude product was crystallized (CH2Cl2/hexanes) to give 4-[(3-n-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl] benzoic acid methyl ester as white crystal (78%): TLC (20% ethyl acetate: 80% hexanes) Rf 0.8; mp 120-121° C.; 1H-NMR (400 MHz, CDCl3) δ7.94 (½ABq, J=8.0 Hz, 2H, ArH), 7.33 (½ABq, J=8.0 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 7.08 (s, 1H, ArH), 5.80 (s, 1H, olefinic), 5.30 (s, 1H, olefinic), 3.90 (s, 3H, OCH3), 2.24 (t, J=8.0 Hz, 2H, CH2), 1.70 (s, 4H, 2CH2), 1.39 (m, 2H, CH2), 1.30 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 0.73 (t, J=7.5 Hz, 3H, CH3), Anal. (C27H34O2) C, H. The ester was hydrolized using the standard conditions of Example 1 to yield 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]benzoic acid (102). Crystallization gave white crystals (83%): TLC (10% MeOH-90% CHCl3) Rf 0.5; mp 263-265° C. 1H-NMR (400 MHz, CDCl3) δ8.00 (½ABq, J=8.0 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 7.08 (s, 1H, ArH), 5.81 (s, 1H, olefinic), 5.31 (s, 1H, olefinic), 2.23 (t, J=8.0 Hz, 2H, CH2), 1.70 (s, 4H, 2CH2), 1.39 (m, 2H, CH2), 1.30 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 0.73 (t, J=7.5 Hz, 3H, CH3), FAB-MS m/z 377 (MH+); Anal. (C26H32O2) C, H.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:15]=2[S:14]1.C(OCC)C.Cl>C(O)C>[ClH:1].[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:9])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:27][C:15]=2[S:14]1
Reactant: CCCSCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCS(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: -35 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
70-75% pure m-chloroperbenzoic acid (4.3 g) is added in the course of approximately 10 minutes to 2-imino-3-(2-propylthioethyl)-6-trifluoromethoxybenzothiazoline (5.87 g) dissolved in absolute ethanol (80 cc) cooled to -35° C. The reaction is continued for 10 minutes at the same temperature. The reaction medium is then added to ethyl ether (300 cc) and treated with 4.2N ethereal hydrogen chloride (4.2 cc). The precipitate formed is filtered off, then taken up in distilled water (50 cc) and neutralized with 1N sodium hydroxide. After extraction with ethyl acetate, drying over magnesium sulphate and concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa), the crude product is purified by chromatography on a silica column, with ethyl acetate and then a mixture of ethyl acetate and methanol (90:10 by volume) as eluents. After conversion to hydrochlorides, 2-imino-3-(2-propylsulphonylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (0.33 g), subliming at about 200° C., and (RS)-2-imino-3-(2-propylsulphinylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (2.63 g), m.p. 125° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:15])[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[N:16]1([C:21](N2C=CN=C2)=[S:22])[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:15][C:21]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[S:22])[S:12][C:13]=2[CH3:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(N)sc2C)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc(-c2nc(NC(=S)n3ccnc3)sc2C)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To 4-(4-methoxyphenyl)-5-methylthiazol-2-amine (0.98 g, 4.45 mmol) in acetonitrile (25 mL) was added di(1H-imidazol-1-yl)methanethione (1.03 g, 5.78 mmol). The reaction was stirred at 50° C. for 3 hours. The reaction was cooled to room temperature and the precipate was filtered. The powder was washed with acetonitrile (2×10 mL) and dried to yield racemic N-(4-(4-methoxyphenyl)-5-methylthiazol-2-yl)-1H-imidazole-1-carbothioamide (1.28 g, 3.87 mmol, 87% yield) as a yellow powder. The product was taken directly to the next step.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14]2)=[C:9]([CH3:22])[CH:8]=1>C(OCC)(=O)C>[CH3:6][C:7]1[CH:8]=[C:9]([CH3:22])[C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]([F:20])([F:21])[F:19])=[N:14]2)=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C)c1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 2.5 g (22 mol) of chlorosulfonic acid and then 1.8 g (7.4 mmol) of 1,3-dimethyl-4-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)benzene. The mixture was stirred at 70° C. for 2 hours. The mixture was cooled to room temperature and then added onto ice in small portions. Thereto was added 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Then, vacuum distillation was conducted to distill off ethyl acetate to obtain a title compound as 2.5 g of brown oil. Yield: 99%