Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:31][CH2:32][C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35].[OH-].[NH4+].FC(F)(F)C1(C(F)(F)F)CO1>CCCCO.CS(C)=O>[F:35][C:34]([F:36])([F:37])[C:33]([CH2:32][NH:31][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: NCC(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Agent: FC(F)(F)C1(C(F)(F)F)CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(NCC(O)(C(F)(F)F)C(F)(F)F)nc21
Reaction time: 72 h
Yield: 23 %

Procedure:
To a stirred solution of 2-fluoro-9-isopropyl-6-[(pyridine-3-ylmethyl)-amino]purine (50 mg, 0,175 mmol) in n-BuOH/DMSO (2.5 ml, 4:1) at room temperature and under an argon atmosphere was added diisopropylethylamine (135 mg, 1.05 mmol) followed by 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropane-2-ol (prepared from the reaction of 30% ammonium hydroxide with 2,2-bis[trifluoromethyl]oxirane). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 3 days. The reaction was followed by LCMS and was gone by only 30%. Additional newly prepared 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropane-2-ol was added and the reaction continued. This addition was done on three more consecutive days to achieve complete conversion. After removal of solvent, the residue was purified by silica gel flash column chromatography to give the title compound as a pale brown powder (19 mg, 23%); δH (CDCl3, 500 MHz) 1.57 (6 H, d, J 7.5, CH[CH3]2), 3.48-3.44 (1 H, m, NHCHHCOH[CF3]2, 3.86-3.81 (1 H, m, NHCHHCOH[CF3]2, 4.62-4.555 (1 H, m, CHMe2), 4.78-4.74 (2 H, m, NHCH2ArH), 5.35 (1H, s, br, OH), 6.36 (1 H, s, br, NH), 7.27-7.22 (2 H, m, ArH), 7.7-7.67 (1 H, m, ArH), 8.5 (1 H, d, J 5, ArH), 8.66 (1 H, s, ArH); δC (CDCl3, 500 MHz) 159.99 (C), 154.63 (C), 149.53 (C), 149.05 (C), 148.6 (CH), 137.79 (C), 135.41 (C), 135.38 (CH), 135 (CH), 123.44 (CH), 75.03 (C), 47.62 (CH2), 46.84 (CH), 42.05 (CH2), 22.1 (2×CH3); m/z 464.2 (M+H)
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:11][CH:12]=[CH2:13])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][O:14][C@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:8]
Reactant: C=CC[C@H](CO[Si](C)(C)C(C)(C)C)OCOCCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@H](CO)OCOCCOC
Temperature: 23 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of 10 (440 mg, 1.4 mmol) and TBAF (1.0 M solution in THF, 4.7 mL, 4.7 mmol) in THF (3 mL) was stirred at 23° C. for 3 h, afterward a saturated solution of NaHCO3 was added, the solvent was removed and the aqueous phase was extracted with CHCl3. The organic extracts were dried (Na2SO4) and the solvent was removed. The residue was purified by flash-chromatography to afford 237 mg (87%) of (R)-2-[(2-methoxyethoxy)methoxy]pent-4-en-1-ol as a colourless oil: [c]D20=−55.0 (c 1.3, CHCl3); 1H NMR (CDCl3) δ 5.85-5.71 (m, 1H), 5.11-5.02 (m, 2H), 4.81 (d, J=7.5 Hz, 1H), 4.75 (d, J=7.5 Hz, 1H), 3.87-3.80 (m, 1H), 3.71-3.61 (m, 3H), 3.59-3.46 (m, 3H), 3.37 (s, 3H), 3.22 (bs, 1H), 2.36-2.19 (m, 2H); 13C NMR (CDCl3) δ 134.1, 117.3, 95.4, 81.0, 71.5, 67.3, 64.8, 58.9, 36.2. To a mixture of the above compound (240 mg, 1.25 mmol), allyl bromide (225 μL, 1.9 mmol) and a catalytic amount of TBAI in THF (12 mL), at 0° C., sodium hydride (60% dispersion in oil, 102 mg, 2.5 mmol) was added in small portions. After 30 min, the reaction mixture was allowed to warm to 23° C. and was stirred at the same temperature for 18 h. Subsequently, the reaction was quenched with a saturated solution of NH4Cl, the organic solvent was removed and the aqueous phase was extracted with CHCl3. The organic extracts were dried (Na2SO4) and the solvent was evaporated. The residue was purified by flash-chromatography (10:1 CHCl3/EtOAc) to afford 229 mg (80%) of 11 as a colourless oil. [α]D20, −5.2 (c 3.1, CHCl3); 1H NMR (CDCl3) δ 5.87-5.79 (m, 2H), 5.34 (dd, J=1.3, 19.1 Hz, 1H), 5.16-5.03 (m, 3H), 4.81 (d, J=7.0 Hz, 1H), 4.77 (d, J=7.0 Hz, 1H), 3.98-3.97 (m, 2H), 3.84-3.81 (m, 1H), 3.72 (t, J=5.0 Hz, 2H), 3.54 (t, J=5.0 Hz, 2H), 3.46-3.44 (m, 2H), 3.38 (s, 3H), 2.35-2.31 (m, 2H); 13C NMR (CDCl3) δ 134.6, 134.3, 117.3, 116.7, 94.6, 75.3, 72.1, 71.9, 71.6, 66.7, 58.9, 36.3.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[N:26](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:26])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution (20 ml) of 4-[5-(4-trifluoromethylphenyl)-2-furyl]benzoic acid -(0.665 g) and N,N-dimethylformamide (0.1 ml) in tetrahydrofuran was added oxalyl chloride (0.209 ml) at 0° C. This mixture was stirred for 10 min., and concentrated. The residue was dissolved in acetonitrile (30 ml), and this solution was added dropwise to 25% aqueous ammonia (50 ml) at 0° C. The mixture was stirred for 10 min. and poured into water. The crystals were collected by filtration and recrystallized from ethanol to give 4-[5-(4-trifluoromethylphenyl)-2-furyl]benzamide (0.506 g, yield 76%) as a colorless crystalline powder. melting point: 263–264° C.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:26][CH:27]=1)#[N:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(Cc3ccc(F)cc3)CC(C1)O2
Temperature: 160 °C
Yield: 62.7 %

Procedure:
N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamide (0.079 g, 0.2 mmol; see step (ii) above) and 1-bromomethyl-4-fluorobenzene (0.040 g, 0.21 mmol) and K2CO3 (0.041 g, 0.3 mmol) were was mixed in a microwave vessel and then heated in the microwave reactor for 15 min at 160° C. The mixture was filtered and put on a SCX-II plug. The plug was washed with DCM, acetonitrile, DCM/MeOH (80:20), after which the product was eluted with DCM:MeOH(NH3-satd.), 80:20. The product was purified on a 9 g Horizon prep. chromatography column (A:DCM(1% MeOH), B:DCM/MeOH(NH3-satd.), 80:20. Gradient 0-25% B, 270 mL (9 mL fractions)), which gave 63 mg (62.7%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]1([CH2:3][CH2:2][Cl:1])[O:18][CH2:17][CH2:16][O:5]1
Reactant: O=C(CCCl)c1ccc2ccccc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: ClCCC1(c2ccc3ccccc3c2)OCCO1

Procedure:
A solution of 1.36 g of 2-chloroethyl-2-naphthyl ketone, 6.05 g ethylene glycol and a crystal of p-toluenesulfonic acid monohydrate in 50 ml of toluene is heated for 8 hours under reflux through a Dean-Stark trap. After cooling, the mixture is neutralized by pouring into excess aqueous potassium carbonate, extracted with 200 ml ether and the organic phase washed, dried (MgSO4), and evaporated to yield 2-(2-naphthyl)-2-(2-chloroethyl)-1,3-dioxolane. Without further purification the crude ketal (1.36 g.) is heated with 1.77 g of imidazole in 2 ml of acetonitrile at 85° overnight. The resulting mixture is evaporated to dryness, treated with water and the product extracted with ether. The extracts are washed well with water, dried (MgSO4), evaporated and the residue chromatographed on silica gel eluting with 5% methanol/dichloromethane to give 0.78 g of 1-[3,3-ethylenedioxy-3-(2-naphthyl)-n-propyl]imidazole.
Reaction SMILES: [Na].C(O[CH:5](OCC)[C:6](=[CH:9]O)[C:7]#[N:8])C.Cl.[CH2:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[NH:23])=[CH:20][CH:19]=1)[CH2:16][CH3:17].Cl>O>[C:7]([C:6]1[CH:5]=[N:23][C:22]([C:21]2[CH:25]=[CH:26][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[N:24][CH:9]=1)#[N:8]
Reactant: CCOC(OCC)C(C#N)=CO
Reactant: CCCc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: CCCc1ccc(-c2ncc(C#N)cn2)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
3.26 G. of the crude sodium salt of hydroxymethylene-cyanacetaldehyde diethylacetal are dissolved in 20 ml. of water with stirring. 4.51 G. of p-n-propylbenzamidine hydrochloride are added and the resulting solution, which reacts alkaline, is adjusted to pH 4-5 with 1 ml. of 3-N hydrochloric acid. After stirring for 5 minutes, the mixture is concentrated to dryness at 50° C. in vacuo and the residue is left to stand at room temperature with 50 ml. of acetic anhydride for 16 hours. Then, the mixture is heated to 100° C. for 1 hour, evaporated in vacuo and the residue (brown oil, partly crystalline) is taken up in methylene chloride and chromatographed on silica gel. Elution with methylene chloride and methylene chloride/2% acetone yields 5-cyano-2-(4-n-propylphenyl)-pyrimidine which is recrystallized from acetone/hexane to a constant melting point and then sublimed in a high vacuum at 120° C, whereby there are obtained colorless crystals of said pyrimidine having a melting point of 125.9°-126.0° C, which on cooling are liquid crystalline (monotropic) at 106.4° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[S:13][C:14]4[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]3=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:8]=2[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41]1[CH2:45]OC[CH2:42]1.ICCC>CN(C=O)C>[C:1]1([C:7]2[N:12]=[C:11]3[S:13][C:14]4[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]3=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:8]=2[CH:26]([CH2:42][CH2:41][CH3:45])[C:27]([O:29][CH3:30])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 94.6 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.185 g; 0.45 mmol), LHMDS 1N in THF (0.495 mL; 0.495 mmol), 1-iodopropane (0.066 mL; 0.675 mmol) in DMF (1.3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.194 g (95%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:11][C:12](=O)[O:13]C(C)(C)C)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][NH:5][CH3:6])[C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CNCCNC
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CNCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(methyl(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35. found 511 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11]1.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1.CCCCCC.O1CCCC1>[OH:31][CH:24]([C:18]1[S:19][C:13]2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11][N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3ccccc3)sc12
Temperature: 25 °C

Procedure:
A solution of lithium diisopropylamide (13.6 mmol) in tetrahydrofuran/hexane (2:1, 22 ml) was added dropwise to a solution of 5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (example 6 step b, 2.00 g) in tetrahydrofuran (24 ml) at −70° C. under nitrogen. Benzaldehyde (2.00 ml) was added and after 15 minutes, the mixture was warmed to room temperature. 1M Hydrochloric acid (50 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The organic extracts were washed twice with 1M hydrochloric acid, twice with saturated sodium hydrogen carbonate solution, then with brine, dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:3 then 1:2 then 1:1), to give the title compound (2.48 g) of which 0.5 g was purified by preparative normal-phase HPLC with gradient ethanol/dichloromethane elution to gave the title compound (0.38 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[N:9]([CH2:17][C:16]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=3[O:14][CH3:13])[C:10]=2[N:11]=1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: COc1ccc(CCl)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)COc3ccc(Br)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A suspension of 6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.412 g, 1.8 mmol) and 2,4-dimethoxybenzyl chloride (0.336 g, 1.8 mmol; freshly prepared according to U.S. Pat. No. 5,817,653) in DMF (5 mL) was treated with Cs2CO3 (1.76 g, 3 eq.). The mixture was stirred at rt for 2 h, partitioned between EA and water. The aq. phase was extracted with EA and the combined org. layers washed with water, and brine, dried over MgSO4 and concentrated. The residue was purified by FC (Hept/EA 1:1) to give the title intermediate as a colourless oil (0.61 g, 90% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:30])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:27][CH:26]4[N:28](C)[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[CH:20]=2)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1(C)C=CC=CC=1.O>[CH2:41]([O:40][C:38]([N:28]1[CH:26]2[CH2:25][CH2:24][CH:23]1[CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:14]3[CH:13]=[N:12][C:11]([NH2:30])=[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=3)[CH:17]=[N:18]1)[CH2:27]2)=[O:39])[CH3:42]
Reactant: CN1C2CCC1CC(n1cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn1)C2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1C2CCC1CC(n1cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn1)C2
Temperature: 110 °C

Procedure:
To a solution of 3-benzothiazol-2-yl-5-[1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (50.8 mg, 0.122 mmol; 1 eq) and K2CO3 (1.2 mg, 0.0087 mmol, 7 mol %) in toluene (3 mL), ethyl chloroformate (67.0 mg, 0.617 mmol, 5 eq) in toluene (1 mL) was added. The solution was heated to reflux for a total of 10 h (temp=110° C.). The residue was dissolved in water. The aqueous mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel [0.5″×10″ column, eluting with CH2Cl2:EtOAc 1:0→2:1→1:1→1:2→0:1]. Fractions containing product were combined and concentrated in vacuo to give the title compound. MS (ES+): m/z=475.13 (100) [MH+]. HPLC: tR=3.41 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([N:16]2[C:20](=[O:21])[N:19]([CH:22]([F:24])[F:23])[C:18]([CH3:25])=[N:17]2)=[C:4]([F:26])[CH:3]=1.[CH3:27][S:28]([NH:31][C:32](=[O:36])[CH:33](Br)[CH3:34])(=[O:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:27][S:28]([NH:31][C:32](=[O:36])[CH:33]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[C:5]([N:16]3[C:20](=[O:21])[N:19]([CH:22]([F:23])[F:24])[C:18]([CH3:25])=[N:17]3)[C:4]([F:26])=[CH:3][C:2]=2[Cl:1])=[CH:10][CH:11]=1)[CH3:34])(=[O:30])=[O:29]
Reactant: Cc1nn(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: CC(Br)C(=O)NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(-c2cc(Oc3ccc(OC(C)C(=O)NS(C)(=O)=O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Yield: 40.1 %

Procedure:
In a manner similar to Step D of Example 1, the reaction of 0.60 g (0.0015 mole) of 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.32 g (0.0014 mole) of N-methylsulfonyl-2-bromopropionamide, and 0.24 g (0.0017 mole) of potassium carbonate in 20 mL of acetone produced 0.3 g of N-methylsulfonyl-2-[4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5 -dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]phenoxy]-propionamide as an oil, Compound 32 of Table 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][CH2:17][CH3:18])=[CH:6][C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.C(O)(C)(C)C.[H-].[Na+]>C1COCC1>[CH2:17]([S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[NH:1][C:2]2=[N:3][CH:4]=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:6]=[C:7]2[N:8]=1)[CH3:18]
Reactant: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Temperature: 80 °C
Yield: 69.7 %

Procedure:
A mixture of N-(2-amino-5-trifluoromethylpyridine-3-yl)-2-ethylsulfanyl-benzamide (200 mg), tert-butylalcohol (1 ml), and THF (9 ml) was stirred with heating at 80° C., then 60% of sodium hydride (in oil, 56 mg) was added thereto. The mixture was stirred with heating at 80° C. for 2 hours, and then 60% of sodium hydride (in oil, 56 mg) was added. The mixture was further stirred with heating at the same temperature for 2 hours, and then to the mixture, 60% of sodium hydride (in oil, 56 mg) was added, and stirred with heating at the same temperature for 2 hours. The reaction mixture was cooled to room temperature, and evaporated to remove the solvent, and then to the mixture, saturated ammonium chloride solution was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 132 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 351).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]([F:34])([F:33])[F:20])=[CH:29][N:28]=2)=[O:31])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)NC(=S)CO1

Procedure:
The title compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A′7A) (108 mg, 0.38 mmol) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [CAS No. 881409-53-6; described in intermediate 49] (94 mg, 0.43 mmol). The compound was obtained as a light yellow foam (156 mg, 76%). MS (ISP): m/z=486.3 [(M+H)+].
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:25])[C@H:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.ClC1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])[N:28]=1.C(N(CC)CC)C>[Pd].CO>[OH:24][C@@H:18]([C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[C:36]3[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=3)[N:30]=[C:29]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[OH:44])[N:28]=2)[CH2:16][CH2:15]1)=[O:25])[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: COC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
4-((R)-2-Hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylic acid benzyl ester (0.52 g, 1.5 mmol) and MeOH (15 mL) were stirred with 10% Pd/C under an H2 atmosphere at ambient pressure overnight. After filtration and evaporation of the solvent the residue was taken up in CH2Cl2, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.40 g, 1.50 mmol) plus triethylamine (0.41 mL, 3.00 mmol) were added. The reaction mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided (R)-methyl 3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate (0.38 g, 57%). LC/MS: m/z 451.1 (M+H)+ at 2.18 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][C:33]=1[F:41]>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)=[C:33]([F:41])[CH:34]=1)(=[O:37])[NH2:38]
Reactant: NC(=O)c1ccc(Br)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)cc4F)ccc3o2)CC1
Yield: 39.2 %

Procedure:
Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.48 mmol) and 4-bromo-3-fluorobenzamide (105 mg, 0.48 mmol) as an off-white solid. M.P.: 194-197° C. MS (m/z): 426.0 [M+H]+.