Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[C:14](=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=4)[CH:15]=3)=[CH:10][N:5]2[N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1([C:46]2[S:47][CH:48]=[C:49]([CH2:51]O)[N:50]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:51][C:49]5[N:50]=[C:46]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[S:47][CH:48]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COc1nn2cc(-c3cc4c(O)cccc4o3)nc2s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cccc4o3)nc2s1
Temperature: 2 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 38G, 0.100 g, 0.349 mmol), triphenylphosphine (0.165 g, 0.627 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.080 g, 0.418 mmol) in a 50 ml flask was maintained under vacuum for 10 min and then purged with nitrogen. Dry tetrahydrofuran (10 mL) was added and the resulting mixture was slightly warmed and maintained in an ultrasonic bath for 5 min. The cooled mixture (still heterogeneous) was treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.113 g, 0.558 mmol) in tetrahydrofuran (2 mL) added dropwise over 1 h. The mixture was then stirred at 2° C. for 4 h. The clear reaction mixture was quenched by the addition of dichloromethane (100 mL) and saturated sodium bicarbonate (10 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel (2.5×12 cm, elution dichloromethane-ethyl acetate 0-3%) followed by crystallization of the desired fraction from ethyl acetate (8 mL) gave 0.028 g (24% yield) of the title material as a white solid. LC (Method A): 2.426 min. HRMS (ESI) calcd for C23H17N4O3S2 [M+H]+ m/z 461.0737. found 461.0926. 1H NMR (CDCl3, 400 MHz) δ ppm: 4.22 (s, 3H), 5.45 (d, J=0.78 Hz, 2H), 6.80 (dd, J=7.04, 1.57 Hz, 1H), 7.15-7.21 (m, 2H), 7.22 (s, 1H), 7.38 (s, 1H), 7.42-7.51 (m, 3H), 7.92 (s, 1H), 7.95-8.03 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[N:23]1(C(N)=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([C:9]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:11])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(CCCc1ccc(Cl)cc1)C(=O)O
Reactant: NC(=O)N1CCCCC1
Product: CC(C)(C)OC(=O)CC(CCCc1ccc(Cl)cc1)C(=O)N1CCCCC1

Procedure:
2[[3-(4-Chlorophenyl)-propyl]-succinic acid 4-tert-butyl ester (WO 95/04033) (5 g, 15.3 mmol) was converted to the corresponding piperidine amide by the method described previously (Example 1, Step G). Yield 4.01 g (67%). 1H-NMR: δ (CDCl3), 7.23 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.3 Hz), 3.68-3.42 (4H, m), 3.12 (1H, m), 2.69 (1H, dd, J=8.4, 16.4 Hz), 2.62-2.49 (2H, m), 2.29 (1H, dd, J=5.6, 16.4 Hz), 1.72-1.33 (10H, m) and 1.41 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:15][C:14]=3[O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[O:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccc(F)cc3c(=O)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A solution of 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzoic acid (7.4 g, 16.8 mmol) in dry DMF (120 mL) was treated with S1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.42 g, 33.5 mmol). The reaction was stirred at ambient temperature overnight. The mixture was poured into brine (300 mL) and extracted with 10% MeOH in EtOAc (3×100 mL). The combined extracts were washed with water (2×400 mL), then brine (2×400 mL), dried over MgSO4, and concentrated to a solid which was purified by chromatography on silica, using 40/55/5 THF/Hex/Et3 N in hexanes, to give 3.4 g (48%) of a yellow solid.
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]2=[N:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:25]([F:28])([F:27])[F:26])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[CH:15][N:9]2[N:8]=1)[CH3:5].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].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>[C:29]([NH:33][C:21](=[O:22])[C:20]1[CH:24]=[C:16]([C:14]2[N:13]=[C:10]3[N:9]([CH:15]=2)[N:8]=[C:7]([O:6][CH2:4][CH3:5])[CH:12]=[CH:11]3)[CH:17]=[CH:18][C:19]=1[C:25]([F:27])([F:28])[F:26])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(C(=O)O)c3)cn2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(C(=O)NC(C)(C)C)c3)cn2n1
Temperature: 80 °C
Yield: 28 %

Procedure:
An 8 mL vial is charged with acetonitrile (0.5 mL), 5-(6-ethoxyimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)benzoic acid (0.035 g, 0.0001 mol), tert-butylamine (0.016 mL), triethylamine (0.055 mL), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.088 g). The mixture is stirred and heated at 80° C. for 16 hr, cooled, concentrated onto celite and purified by silica (0-100% EtOAc in Hexanes) to give the title compound (0.011 g, 28% yield). LCMS m/z=407.5 [M+H]+, tR=2.74 min. (compound same as Example 211)
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:18][CH2:17][CH:16]2[CH:7]([C:8]3[C:13]([C:14]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)=[N:15]2)=[CH:12][C:11]([O:28][CH3:29])=[C:10]([O:30][CH3:31])[CH:9]=3)[CH2:6]1)(=[O:3])[CH3:2].[CH3:32][S:33][C:34]([NH2:36])=[NH:35].OS(O)(=O)=O.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:29][O:28][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:30][CH3:31])[CH:7]1[CH:16]([CH2:17][CH2:18][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]1)[N:15]=[C:14]2[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:36][C:34](=[NH:35])[S:33][CH3:32])=[O:25])=[CH:21][CH:20]=1
Reactant: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)O)cc1
Reactant: CSC(=N)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)NC(=N)SC)cc1
Reaction time: 16 h
Yield: 102.3 %

Procedure:
3.051 g of 4-((2RS,4aRS,10bRS)-2-acetoxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-benzoic acid (compound B1), 3.00 g of S-methylisothiourea-sulfate and 10 mg of 4-dimethylaminopyridine are dissolved in 50 ml of acteonitril, than 1.80 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.23 ml of N-ethyl-diisopropylamin are added. After stirring for 16 hours the solvent is removed. The residue is dissolved in 20 ml of water and extracted with dichloromethane. After drying the combined organic layers with magnesium sulfate the solvent is removed to yield 3.652 g of the title compound as a yellow foam which is directly submitted to further reaction without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[N:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>C1COCC1.ClCCl.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([Cl:26])=[CH:28][CH:29]=2)[N:7]=1
Reactant: Fc1cccc(F)c1-c1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1-c1nc(Cl)nc(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 262 mg (1 mmol) of (2,4-dicholoro-6-(2,6-difluorophenyl)-1,3,5-triazine (XXV) in 3 mL of dry THF was added at room temperature 129 mg (1 mmol) of iPr2NEt (Hunig's base) in 0.5 mL of dry THF. To this was added dropwise a solution of 127 mg (1 mmol) of 4-chloroaniline in 1.5 mL of dry THF. The reaction was stirred for 12 hr at room temperature and poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated. The aqueous layer was extracted twice with additional ethyl acetate and the combined organic layers were dried over magnesium sulfate. Filtration and evaporation provided a viscous film. The material was redissolved in dichloromethane and loaded onto a small plug of silica gel in a filter funnel. The silica gel was eluted with 10% ethyl acetate in hexanes and then 20% ethyl acetate in hexanes to afford 140 mg of the desired product (XXVI). ESI/MS 353.0, 354.9, 356.9 (M+H), 351.0, 353.0, 355.0 (M−H).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[Br:15]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:6][C:7]1[C:12]([Br:15])=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: COc1ccc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N)c(Br)n1
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
Sodium acetate (1.6 g) was added to a solution of 5-amino-2-methoxypyridine (2.5 g) in acetic acid (15 ml). To the resulting solution bromine (3.0 g) was added dropwise, and the mixture was stirred for 20 min., and then added to a solution of sodium hydroxide (10 g) in water (100 ml). The product was extracted with ethyl acetate (50 ml), dried (anhydrous magnesium sulfate), and concentrated in vacuo. The product was purified over a silica gel column (ethyl acetate/hexane, 1:4) to give 2.7 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCOc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOc1ccncc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 5.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), 4-(2-chloroethoxy)pyridine hydrochloride (155 mg, 0.79 mmol) and potassium carbonate (260 mg, 1.9 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours, allowed to cool to ambient temperature and stirred for a further 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline (20 mg, 7%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].C[Al](C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][C:20]=1[C:31]#[N:32]>C1(C)C=CC=CC=1.CCCCCCC.C(Cl)Cl.CO>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([NH:10][C:31]([C:20]2[CH:21]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:23]=[CH:24][C:19]=2[F:18])=[NH:32])[CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1cc(-c2ccccc2)ccc1F
Reactant: Nc1cccc(C2OCCCO2)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(Nc1cccc(C2OCCCO2)c1)c1cc(-c2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 3-(1,3-dioxan-2-yl)aniline (55) (336 mg, 1.87 mmol) in toluene (7.5 mL) cooled to 0° C. was added a 2M trimethylaluminum solution in heptane (1.32 mL) dropwise and the resulting mixture was stirred at ambient temperature for 3.5 hours. The nitrile (54) (370 mg, 1.88 mmol) in toluene (7.5 mL) was added and the reaction heated to 70° C. overnight. The reaction was then cooled, poured onto a slurry of silica in DCM/MeOH and the organics flushed through with further DCM/MeOH. The filtrate was concentrated in vacuo and the residue purified by column chromatography using a gradient of EtOAc in heptane (5-100%) to yield the title compound. Yield: 378 mg, 53%; LC-MS tr 1.32 min; HPLC Purity: 71%; MS (ES+) m/z 377 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:20]C(=O)C1C=CC=CC=1)=[N:9]2.C1CCN2C(=NCCC2)CC1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:20])=[N:9]2
Reactant: CO[C@H]1CC[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccccc2F)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CO[C@H]1CC[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)C1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,7S*,8aS*)-8a-(2-Fluorophenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 57-(7) (268 mg) was dissolved in methanol (8 mL). Then, DBU (202 μL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for four hours and 15 minutes. Then, the reaction solution was stirred at 64° C. for 13 hours and 30 minutes. Thereafter, the reaction solution was stirred with heating under reflux for nine hours and 30 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (150 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].C(O[C:15](=N)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(O)(=O)C>C(OCC)C>[CH2:20]([O:19][C:17]([CH2:16][C:15]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1)=[O:18])[CH3:21]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CCOC(=N)CC(=O)OCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), ethyl 3-ethoxy-3-iminopropionate and glacial acetic acid (15 mL) was stirred 30 minutes at 110° C. under nitrogen. The mixture was poured over crushed ice (50 mL) and stirred 30 minutes to give a dark yellow oil. The mixture was stirred while diethyl ether (25 mL) was added to give a gray precipitate. The precipitate was isolated by filtration, washed several times with diethyl ether and dried under vacuum to provide 2-ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); 1H-NMR (300 Mhz, DMSO-d6): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J=7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J=7.1 Hz).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.I[C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=1>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>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Nc1cncc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1cncc(-c2nccs2)c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
The mixture of 2-tributylstannylthiazole (2.24 g, 6.00 mmol), 5-iodopyridin-3-ylamine (1.10 g, 5.00 mmol) and Pd(Ph3P)4 (580 mg, 0.5 mmol) in 50 mL toluene was degassed using Ar. The mixture was then stirred under Ar at 115° C. for 3 h. The mixture was concentrated and subjected to flash column (0 to 7% MeOH in DCM) to isolate 5-(thiazol-2-yl)pyridin-3-amine (740 mg, 84% yield).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:30])(=[S:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:30]=[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[S:29][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)c1cccnc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2sc(-c3cccnc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone from Step 2 (0.732 g, 1.97 mmol) in acetonitrile (20 mL) in a 50 mL round bottom flask was added thionicotinamide (0.273 g, 1.97 mmol) with stirring. The resulting solution was heated to reflux for 1 hour and additional 2-bromo-1-(4-fluorophenyl)-3-(methylsulfonylphenyl)ethanone (0.031 g, 0.05 mmol) was added and stirred at ruflux for an additional hour. The reaction was cooled to room temperature and concentrated in vacuo yielding an orange semi-solid. This was purified by flash chromatography (2:1 hexane:ethyl acetate with 1% acetic acid). The product fractions were combined, toluene added, and the resulting solution reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(3-pyridyl) thiazole as a pale yellow crystalline solid (0.351 g, 43%): mp 143°-146° C. 1H NMR (CDCl3) 400 mHz δ9.20 (d, J=1.81 Hz, 1H), 8.68 (dd, J=1.46, 4.89 Hz, 1H), 8.30 (dr, J=2.00, 9.42 Hz, 1H), 7.91 (d, J=8.55 Hz, 2H), 7.60-7.52 (m, 4H), 7.42 (m, 1), 7.05 (t, J=8.70 Hz, 2H), 3.10 (s, 3H). MS (EI): m/z 410 (M+). HRMS Δ=-4.3
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])[CH:10]=[CH:11][C:12]=1[OH:13]>>[Br:6][C:7]1[C:12]([OH:13])=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=[C:9]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])[CH:8]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1ccc(O)c(Br)c1
Reactant: O=S(=O)(O)Cl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To 47 ml of chlorosulfonic acid, cooled to −10° C. in a pressure vessel under a nitrogen atmosphere, was slowly added 4-(3-bromo-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (20.25 g). The mixture was allowed to reach room temperature. After stirring for 17 h, the mixture was poured onto 800 ml of crushed ice and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ethyl acetate. The solids were collected and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccc(Br)cc1

Procedure:
In close analogy to the procedure described above, 2-(4-bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [C:1]1([S:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:18]>C1C=CC=CC=1>[C:12]1([C:8]2[S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:9]=2[NH:18][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C(Sc1ccccc1)c1ccccc1
Reactant: N
Solvent: c1ccccc1
Product: c1ccc(Nc2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
3.0 g of anilide of phenylthio-phenyl acetic acid (colourless needles in a mixture of benzene and petroleum ether mp 142°-143°) in 130 g of polyphosphoric acid are heated to 100° for 19 hours. The cooled reaction mixture is poured onto water, made alkaline by concentrated ammonia and extracted with methylene chloride. By drying over sodium sulphate and evaporating the extracts of methylene chloride, 1.7 g (60.0% of theory) of yellow oil are obtained which are recrystallized in ethanol: 1.5 g (45% of theory) of yellow crystals, mp 150°-151° (ethanol).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[N:28]=[CH:27][S:26][C:12]=3[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])[N:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[N:28]=[CH:27][S:26][C:12]=3[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])[N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(C(F)(F)F)c3)c3ncsc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nc(Nc3cccc(C(F)(F)F)c3)c3ncsc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a stirred solution of methyl 3-(7-(3-(trifluoromethyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (100 mg, 0.23 mmol) in 3 mL of THF and 3 mL of methanol was added a solution of sodium hydroxide (46.5 mg, 1.16 mmol) in 1 mL of water at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. HCl was added until pH=4. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1)) to give 3-(7-(3-(trifluoromethyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (65 mg, 67.2%) as a pale yellow solid. 1H NMR (300 MHz, DMSO): δ 13.15 (brs, 1H), 10.65 (s, 1H), 9.46 (s, 1H), 9.00 (s, 1H), 8.67 (s, 1H), 8.60 (d, 1H, J=7.8 Hz), 8.26 (d, 1H, J=7.8 Hz), 8.10 (d, 1H, J=7.5 Hz), 7.68-7.63 (m, 2H), 7.49 (d, 1H, J=7.8 Hz). LC-MS: 417 [M+H]+, 415 [M−H]−, tR=1.65 min. HPLC: 95.14% at 214 nm, 95.28% at 254 nm, tR=7.71 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4](CC#N)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:15][C:16]([OH:18])=[O:17]>O.OS(O)(=O)=O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(OC)c(CC#N)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Br)c(OC)c(CC(=O)O)c1
Yield: 55 %

Procedure:
A solution of (3-Bromo-2,5-dimethoxy-phenyl)-acetonitrile 54 (5.2 g, 20.4 mmol) in water (10 ml), conc H2SO4 (10 ml), and AcOH (30 ml) was heated to 100° C. After 3 hr the reaction was cooled; and poured into water. The aqueous layer was extracted with EtOAc which was then dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (50% EtOAc/Hex) to give a solid (2.8 g, 55%): Mp=62–65° C.; 1H NMR (DMSO-d6) δ 12.45 (br s, 1 H), 7.09 (d, 1 H, J=2.9 Hz), 6.87 (d, 1 H, J=3.0 Hz), 3.72 (s, 3 H), 3.66 (s, 3 H), 3.59 (s, 2 H); MS 273/27 (M−H)−.