Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:17][CH2:16]1.O>CN(C=O)C>[N:1]1([CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[Cl:8])([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[OH:17])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Fc1ccc(C2(c3ccccc3Cl)CO2)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
1,2,4-Triazole (0.04 mol) was added portionwise to sodium hydride (0.04 mol) in DMF (40 ml) and the solution stirred at room temperature until effervescence ceased. 1-o-Chlorophenyl-1-p-fluorophenyl ethylene oxide (0.02 mol) in DMF (10 ml) was added dropwise and the solution stirred at 80° for 4 hours. The solution was poured into water and triturated with petroleum ether to give a white crystalline solid which was filtered off and dried. Recrystallisation from petroleum ether (60°-80°)/methylene chloride gave the title compound (70%) as a white crystalline solid, m.p. 115°-116°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.1 was used with 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 3-methoxy-benzoyl chloride (2 mmol) to obtain a residue. The residue was chromatographed on silica gel eluting sequentially with ethyl acetate and then 6% methanol in dichloromethane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl>[Cl:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)Nc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Reaction time: 1 h

Procedure:
50 ml of chloroform was added to 1.30 g of 4-(4-aminophenyl)-2,6-diphenylpyridine obtained in Reference Example 3, and a solution containing 0.32 ml of chloroacetyl chloride in 10 ml of chloroform was dropwise added thereto with stirring while ice cooling. Stirring was continued at room temperature for further one hour. The reaction solution was washed successively with an aqueous sodium bicarbonate saturated solutions, water and an aqueous sodium chloride saturated solution in this order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residues were recrystallized from ethyl acetate-n-hexane, whereby 1.33 g of 2-chloro-N-[4-(2,6-diphenyl-4-pyridyl)phenyl]acetamide was obtained.
Reaction SMILES: FC(F)(F)CCS(N([C@@H](CCC=C)C(OC)=O)C)(=O)=O.[CH2:21]([O:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([N:31]([C@@H:33]([CH2:38][CH:39]=[CH2:40])[C:34]([O:36]C)=[O:35])[CH3:32])=[O:30])[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([N:31]([C@@H:33]([CH2:38][CH:39]=[CH2:40])[C:34]([OH:36])=[O:35])[CH3:32])=[O:30])[CH3:22]
Reactant: C=CC[C@@H](C(=O)OC)N(C)C(=O)c1sccc1OCC
Agent: C=CCC[C@@H](C(=O)OC)N(C)S(=O)(=O)CCC(F)(F)F
Product: C=CC[C@@H](C(=O)O)N(C)C(=O)c1sccc1OCC
Yield: 89 %

Procedure:
Step N (2): Same procedure as Step A (3). (S)-Methyl 2-(3,3,3-trifluoro-N-methylpropylsulfonamido)hex-5-enoate from Step N (1) was subjected to the ester hydrolysis protocol. The procedure provided 68 mg (89% yield) of the title compound as a colorless oil. LC-MS (M+H)+=284.27.
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH2:32][C:31]3([CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>C(Cl)(Cl)Cl>[O:30]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33]2)[CH2:32][C:28]([C:27]#[C:26][C:22]2[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=2)=[N:29]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#Cc3cccc(O)c3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Solvent: ClC(Cl)Cl
Product: Oc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Yield: 84.8 %

Procedure:
The title compound was synthesized following the method reported for the Compound 1c, substituting Compound 1b with Compound 39a and running the reaction in chloroform. The crude brownish oily residue was used without further purification in the next reaction step. Yield: 84.8%.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[CH:5][C:6]2[N:7]([N:10]=[C:11]([CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[N:12]=2)[C:8]=1[CH3:9])#[N:2].O=P(Cl)(Cl)[Cl:23].CO.N>O>[Cl:23][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[N:7]2[N:10]=[C:11]([CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[N:12]=[C:6]2[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCC(CC)c1nc2cc(O)c(C#N)c(C)n2n1
Agent: N
Solvent: CO
Solvent: O
Product: CCCCC(CC)c1nc2cc(Cl)c(C#N)c(C)n2n1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
272 g of 6-cyano-2-(1-ethylpentyl)-7-hydroxy-5-methyl[1,2,4]triazolo[2,3-a]pyridine were introduced into 250 g of phosphorus oxytrichloride and stirred at 105° C. for 4 hours. Then 250 g of methanol were added dropwise, the mixture was briefly boiled and 250 ml of water were run in. The solution was cooled and, at 10° to 20° C., the pH was adjusted to 7.5 with aqueous ammonia, when the target product precipitated. It was filtered off with suction, washed with water and dried at 50° C. under reduced pressure. 264 g of the compound of the formula ##STR11## were obtained. A sample recrystallized from ethanol/cyclohexane has a melting point of 95° to 96° C. and the following analysis:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2([NH:33]C(=O)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]2)=[CH:19][CH:18]=1.Cl>C(O)C>[NH2:33][C:25]([CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:3]2[CH:4]=[CH:5][C:6]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)=[CH:7][C:2]=2[F:1])=[CH:22][CH:21]=1)([CH2:30][OH:29])[CH2:26][OH:27]
Reactant: COc1cccc(Sc2ccc(-c3ccc(CCC4(NC(C)=O)COC(C)(C)OC4)cc3)c(F)c2)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)c1
Temperature: 75 °C
Reaction time: 7 h
Yield: 94 %

Procedure:
N-(5-{2-[2′-Fluoro-4′-(3-methoxyphenylthio)biphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (0.26 g) was dissolved in ethanol (4 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 75° C. for 7 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (205 mg) as brown crystals.
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CN(CCN(C)C)C.[Li]CCCC.[CH3:19][Sn:20](Cl)([CH3:22])[CH3:21]>CCCCCC>[CH3:19][Sn:20]([CH3:22])([CH3:21])[C:2]1[Se:1][C:5]([Sn:20]([CH3:22])([CH3:21])[CH3:19])=[CH:4][CH:3]=1
Reactant: c1cc[se]c1
Reactant: C[Sn](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Sn](C)(C)c1ccc([Sn](C)(C)C)[se]1
Temperature: 0 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of selenophene (7.4 g, 56.5 mmol) in a solution of anhydrous hexane (90 ml) and TMEDA (17.4 g, 150 mmol) at 0° C. under nitrogen is added a solution of n-BuLi (55 ml of a 2.5M solution in hexanes, 137.5 mmol) dropwise over 5 min. The resulting solution is refluxed for 30 min and then cooled to 0° C. and trimethyltin chloride (25.6 g, 129 mmol) is added at once as a solid. The resulting solution is allowed to warm to room temperature and stirred at that temperature for 20 h. The solution is quenched with water (100 ml), and ethyl acetate (100 ml) is added. The layers are separated and the organic layer is washed with further water (4×100 ml), brine (100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting solid is recrystallized from acetonitrile four times to afford the product as white needles (25.8 g, 83%). M/Z cluster centered at 456 (M+). Found C, 26.3; H, 4.6. Calc. for C10H20SeSn2 C, 26.3; H, 4.2. 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 2H), 0.37 (s, 18H). 13C NMR (75 MHz, CDCl3) δ 150.2, 138.7, −7.7.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[C:6]([CH:7]=[O:8])=[C:2]([Cl:1])[N:3]=[C:4]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Yield: 71.5 %

Procedure:
3.0 g of 4-chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull. 1976, 24(5), 960), 7.0 g of 4-bromobenzyl bromide and 11.7 g of K2CO3 are stirred at RT for 20 h in 200 ml of DMF. The reaction mixture is then poured onto 500 ml of water, and the precipitate is filtered off with suction and chromatographed on silica gel using DIP. 3.9 g of an amorphous foam are obtained.
Reaction SMILES: BrC1C=C(C=CC=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.Cl.OC1C=CC(C(=N)OC)=CC=1>CO>[CH:17]1([N:16]2[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=[C:12]2[C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Agent: COC(=N)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Yield: 143.6 %

Procedure:
Ethyl 3-amino-4-cyclohexylaminobenzoate (130 g) obtained in Example 1, Step 3, and methyl 4-hydroxybenzimidate hydrochloride (139 g) were added to methyl alcohol (1500 ml), and the mixture was refluxed under heating for 4 hr. The reaction mixture was allowed to cool and the precipitated crystals were collected by filtration to give the title compound (131 g, yield 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[F:24][C:25]([F:30])([F:29])[C:26](Cl)=[O:27].FC(F)(F)C(O)=O>C(O)C>[N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:6][C:26](=[O:27])[C:25]([F:30])([F:29])[F:24])([O-:3])=[O:2]
Reactant: O=C(Cl)C(F)(F)F
Reactant: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)F

Procedure:
A solution of 25.1 g. of 2,6-dinitro-4-trifluoromethylaniline in 100 ml. of pyridine was treated with trifluoroacetyl chloride, which has been prepared from 10 ml. of trifluoroacetic acid. Ethanol was added to the resulting mixture until it was homogeneous, and the reaction mixture was then evaporated under vacuum. The residue after evaporation was washed with water, dried, dissolved in acetone, and filtered. Chloroform was added to the filtrate until the product precipitated. The precipitate was separated by filtration and dried to obtain the purified intermediate, 2',6'-dinitro-4'-trifluoromethyl-2,2,2-trifluoroacetanilide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:15][CH:16]([CH3:19])[CH2:17]Cl.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:15][CH:16]([CH3:19])[CH2:17][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: CCCCC(C)(C)c1ccc(CC(C)CCl)c(Br)c1
Solvent: ClC(Cl)Cl
Product: CCCCC(C)(C)c1ccc(CC(C)CN2CCCCC2)c(Br)c1
Temperature: 150 °C
Yield: 47.3 %

Procedure:
A mixture of 50 g of XIII and 38.3 g of piperidine was heated at 150° C. for 7 hours. The mixture was cooled and then taken up in CHCl3, and the solution was washed with dilute NaOH and then with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 27 g of (XIV) of boiling point 170°-171° C./0.1 mbar.
Reaction SMILES: F[C:2]1([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH2:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][CH2:3]1.C1C[O:22]CC1>O.[Pd]>[NH2:16][C:11]1[CH:12]=[N:13][N:14]([CH3:15])[C:10]=1[C:2]12[O:6][CH:7]([CH2:8][CH2:9]1)[CH:5]([OH:22])[CH2:4][CH2:3]2
Reactant: C1CCOC1
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC2OC2CC1
Agent: [Pd]
Solvent: O
Product: Cn1ncc(N)c1C12CCC(O)C(CC1)O2
Temperature: 40 °C

Procedure:
To a solution of 5-(4-fluoro-8-oxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-1H-pyrazole (100 mg, 0.39 mmol) in THF (25 mL) and water (5 mL) was added 10% palladium on carbon (10 mg). The mixture was heated at 40° C. under an atmosphere of H2 (400 psi) for 3 hr. The mixture was filtered through Celite® washing with MeOH (30 mL) and concentrated under reduced pressure to give 5-(4-amino-1-methyl-1H-pyrazol-5-yl)-8-oxabicyclo[3.2.1]octan-2-ol as an orange solid (105 mg, quantitative). This solid (105 mg, 0.44 mmol) was dissolved in DCM (20 mL) and DIPEA (1 mL, 5.74 mmol) was added, followed by 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (161 mg, 0.45 mmol) and PyBOP (535 mg, 1.03 mmol). The reaction mixture was stirred at room temperature for 18 hr before being quenched with water (20 mL), extracted with DCM (100 mL), dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (80-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-8-oxabicyclo[3.2.1]octan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a colourless oil (635 mg, 54%). To a solution of this oil (160 mg, 0.28 mmol) in MeOH (5 mL) was added HCl in dioxane (4 M, 3.6 mL, 14.4 mmol). The reaction mixture was stirred at room temperature for 18 hr. The solvents were removed under reduced pressure before being purified via preparative HPLC, then dissolved in CHCl3/MeOH mixture (10 mL) and passed through an SCX cartridge, eluting with 3N NH3 in MeOH. The solvents were removed under reduced pressure to give 106 as a pale pink solid (31 mg, 24% over three steps). 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.25 (s, 1H), 7.32-7.26 (m, 1H), 7.02 (t, J=8.8 Hz, 2H), 6.12 (s, 2H), 4.59-4.55 (m, 1H), 4.12-4.05 (m, 1H), 3.85 (s, 3H), 2.42-2.33 (m, 1H), 2.22-1.89 (m, 6H), 1.62-1.56 (m, 1H), 1.50-1.45 (m, 1H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: C(S)CCCCCCCCCCC.CC([O-])(C)C.[K+].[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]2[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][C:34]=2[Cl:41])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=2[Cl:41])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCCCCCS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Temperature: 110 °C
Reaction time: 6 h
Yield: 85.2 %

Procedure:
To a solution of 1 dodecanethiol (12.7 mL; 52.86 mmol) in dry DMF (50 mL), was added KOtBu (5.93 g; 52.86 mmol) at 0° C. After complete addition the mixture was allowed to slowly come to RT (˜30 min), and then 4-benzyl-2-(2-chloro-4-methoxy-phenyl)-morpholine (5.60 g; 17.62 mmol) was added. The resulting mixture was stirred at 110° C. for 6 hours. After cooling to RT, EtOAc was added and the resulting mixture was washed with 5% aqueous NaHCO3, water and brine; dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2CL2/MeOH 99:1) to afford 4-(4-benzyl-morpholin-2-yl)-3-chloro-phenol (4.56 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([N+:21]([O-])=O)[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].Cl>CCO.O.[Fe]>[NH2:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([Br:1])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6]
Reactant: COCCOCCOCCNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COCCOCCOCCNC(=O)c1cc(N)cc(Br)c1
Temperature: 75 °C

Procedure:
Iron powder (5.90 g, 106 mmol) was added to a solution of the product from step (i) above (8.24 g, 20.43 mmol) and concentrated HCl (2 mL, 23.40 mmol) in EtOH (65 mL) and water (15 mL). The mixture was heat at 75° C. (block temperature) for 1 h. Then, the reaction was cooled to rt, before being diluted with water (30 mL), filtered and concentrated in vacuo. The residue was basified (NaHCO3) then partitioned between EtOAc (350 mL) and water (275 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford an orange oil that was purified by chromatography on silica gel (220 g column, 0-5% MeOH in DCM) to afford the sub-title compound (5.25 g) as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])C.[CH3:24][O-:25].[Na+]>>[CH3:1][O:3][C:4](=[O:23])[C:5]1[C:10]([O:25][CH3:24])=[CH:9][C:8]([C:12]2[C:13]([CH2:20][CH3:21])=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:18][CH3:19])=[N:7][C:6]=1[CH3:22]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Reactant: C[O-]
Agent: [Na+]
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C)n1
Temperature: 65 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (165 mg, 0.5 mmol) and sodium methoxide (0.5 M in methanol, 4 mL, 2.0 mmol) is heated at 65° C. for 16 hours. The volatile material is removed in vacuo and the residue is partitioned between ethyl acetate (50 mL) and water (20 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 mL). The combined organic extract is dried and concentrated in vacuo. The crude product is purified by PTLC (hexanes/ethyl acetate 4:1) to give 6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-nicotinic acid methyl ester. 1H NMR: (CDCl3) 7.26 (m, 2H), 7.13 (d, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 2.56 (s, 3H), 2.32 (m, 4H), 1.04 (t, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.CN(C)CCCN=C=NCC.[CH3:40][C:41]1[N:42]=[C:43]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[S:44][C:45]=1[C:46](O)=[O:47]>C(OCC)(=O)C.C(OCC)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]1[CH:17]=[C:7]([C@H:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:46]([C:45]3[S:44][C:43]([C:49]4[CH:50]=[CH:51][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:53][CH:54]=4)=[N:42][C:41]=3[CH3:40])=[O:47])[CH2:2]2)[CH:8]=[CH:9][C:10]=1[CH3:18])[CH3:16]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Reactant: CCOC(=O)c1cc([C@H]2CCCNC2)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1cc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.6 %

Procedure:
(R)-ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid (Example 9; 2.13 g, 5.36 mmol) was dissolved in 100 mL ethyl acetate and washed with 100 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 20 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (2.05 g, 10.72 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (1.69 g, 5.90 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 72 h. The reaction was diluted with 200 mL diethyl ether and washed with water (100 mL), saturated aqueous NaHCO3 (2×100 mL), 0.5 N HCl (2×100 mL), water (100 mL), and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid ethyl ester (2.62 g, 95%) as a clear oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][CH:30]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=[C:2]([C:33]3[N:34]=[C:29]([NH2:28])[CH:30]=[CH:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cccc(N)n2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc(N)n4)nc3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[2,3-d]pyrimidine (0.44 mM) and 6-aminopyridine-2-boronic acid pinacol ester were coupled using General Procedure A to give 297 (TFA salt) after reverse-phase HPLC purification. MS (Q1) 491 (M+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[C:2]([F:1])[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(OC2CCCC2)cc1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
To a solution of compound (8) (0.50 g, 2.5 mmol) in dry DMF (5 mL), potassium carbonate (1.2 g, 8.8 mmol), and bromocyclopentane (0.32 g, 3.0 mmol) were added and stirred at 60° C. for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (300 mL) followed by washing with water and drying (over sodium sulfate). The solvent was distilled off, and the residue was dissolved in dichloromethane and washed with a 1 M-aqueous solution (30 mL) of sodium hydroxide. The organic layer was dried (over sodium sulfate) and distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional hydrolysis to give 0.56 g (84%) of compound (14) of interest as white solid.