Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[CH3:29][C:27]1[CH:26]=[CH:25][C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:28]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(C(=O)Nc2ccccc2)c(N)c1
Product: Cc1ccc(C(=O)Nc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (150 mg, 0.84 mmol) was reacted with the product from Example 95c (190 mg, 0.84 mmol) for 6 h following the procedure from Example 1g giving the crude title compound which was purified by silica gel column chromatography eluting with 50:1 CH2Cl2/MeOH providing the title compound (210 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.40 (s, 3H), 2.68 (s, 3H), 6.62 (d, J=6.9 Hz, 1H), 6.98 (t, J=7.3 Hz, 1H), 7.19 (t, J=7.3 Hz, 2H), 7.36 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.52 (d, J=7.3 Hz, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 8.40 (d, J=6.9 Hz, 1H), 8.94 (d, J=8.8 Hz, 1H); MS (ESI+) m/z 369 (M+H), ESI− m/z 367 (M−H).
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([S:24]([NH:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:19][C:18]([S:38]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48]C)=[O:47])=[CH:44][CH:43]=2)(=[O:40])=[O:39])=[CH:17]3)(=[O:13])=[O:12])=[CH:6][CH:5]=1.C(O)(=O)C.[OH-].[Na+:58]>C(O)C>[Na+:58].[Na+:58].[Na+:58].[C:20]1([S:24]([NH:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O-:34])=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:25])[C:21]2[C:16](=[CH:15][C:14]([S:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([O-:52])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:13])=[CH:23][CH:22]=2)[CH:17]=[C:18]([S:38]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([O-:48])=[O:47])=[CH:50][CH:51]=2)(=[O:40])=[O:39])[CH:19]=1
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4ccc(C(=O)OC)cc4)cc(S(=O)(=O)Nc4ccc(C(=O)OC)cc4)cc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C([O-])c1ccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4ccc(C(=O)[O-])cc4)cc(S(=O)(=O)Nc4ccc(C(=O)[O-])cc4)cc3c2)cc1
Reaction time: 0.75 h

Procedure:
A 9.0 g portion of the product of Example 7 is dissolved in 46.5 ml of 2N sodium hydroxide and stirred for 45 minutes. The solution is neutralized with 2.7 ml of glacial acetic acid and diluted with 200 ml of ethanol. A yellow solid separates which is collected by filtration, washed with ethanol and ether, and dried to give 8.7 g of the product of the Example.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([O:21][C@H:22]5[C@H:28]([F:29])[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl-].[CH3:38][Zn+].[NH4+].[Cl-].O>C1COCC1.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>[F:29][C@H:28]1[C@H:22]([O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:6]4[CH:7]=[C:2]([CH3:38])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:23][CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:27]1
Reactant: C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(Br)cn45)nc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2nnc(-c3ccc4cccc(O[C@@H]5CCN(C(=O)OC(C)(C)C)CC[C@H]5F)c4n3)n2c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (trans)-tert-butyl 4-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (0.125 g, 0.225 mmol) and Pd(PPh3)4 (0.0519 g, 0.0449 mmol) in 1.9 mL THF was added 2M methyl zinc chloride in THF (0.225 mL, 0.449 mmol) by syringe, and the reaction mixture was heated in an 80° C. reaction block. After 6 hours, the reaction mixture was cooled to ambient temperature and saturated NH4Cl and water were added, causing a precipitate to form. The solids were isolated by vacuum filtration through qualitative filter paper, rinsed with water, air dried, and dried in vacuo. The crude was purified on silica gel (1-8% MeOH in DCM gradient) to give the racemic (trans)-product. The resulting mixture was separated by chiral HPLC using a Chiracell OJ-H column, 9.5% EtOH in hexanes, flow rate 16 mL/min to give Peak 1 trans-product (0.018 g, 16%, 99% ee) as a white solid, and Peak 2 trans-product (0.014 g, 13%, 92% ee) as a white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[C:11]([OH:19])[CH:10]=1)=[O:7])([OH:3])=[O:2].[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CO>[CH2:20]([NH:26][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][C:11]=1[OH:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN
Reactant: COC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O
Solvent: CO
Product: CCCCCCNC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O

Procedure:
Methyl 4-(3-carboxy-propionylamino)-2-hydroxybenzoate from Example 2 (1 g) is dissolved in 15 mL of methanol. n-Hexylamine (5 mL) is added to this solution, and the reaction mixture is brought to mild reflux for 2 days. Solvents are removed under vacuum and residue acidified using 1 N HCl. N-n-hexyl 4-(3-carboxy-propionylamino)-2-hydroxybenzamide precipitate is collected, washed with water, and dried.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])(O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(O)(c2cccc(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CC=C(c2cccc(F)c2F)CC1
Temperature: 30 °C
Yield: 92.7 %

Procedure:
The compound (8) (215.1 g), p-toluenesulfonic acid (6.5 g) and toluene (500 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (500 ml) and toluene (500 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The product obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and dried, giving 186.6 g of 4-pentyl-(2,3-difluorophenyl)-cyclohexene (9). The yield based on the compound (8) was 92.7%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(OC)c(Nc2nc(Cl)nc3ccccc23)c1
Reactant: CI
Product: COc1ccc(OC)c(N(C)c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (78% yield). 1H NMR (CDCl3): 7.72-7.75 (m, 1H), 7.56 (ddd, J=8.4, 5.7 and 2.1 Hz, 1H), 6.98-7.00 (m, 2H), 6.92-6.92 (m, 2H), 6.78-6.79 (m, 1H), 3.75 (s, 3H), 3,58 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[Br:17]Br>CC(O)=O>[Br:17][CH:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][C:13]1=[O:15]
Reactant: BrBr
Reactant: COc1ccc(C2CC(=O)CC(=O)C2)cc1
Solvent: CC(=O)O
Product: COc1ccc(C2CC(=O)C(Br)C(=O)C2)cc1

Procedure:
To a stirred solution of 5-(4-methoxyphenyl)cyclohexane-1,3-dione (5 g, 22.6 mmol) in AcOH (40 mL) at r.t. was added bromine (3.61 g, 1.18 mL, 22.6 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound in quantitative yield as a white solid. δH (DMSO-d6) 7.24 (2H, d, J 8.6 Hz), 6.87 (2H, d, J 8.6 Hz), 3.72 (3H, s), 3.31-3.21 (1H, m), 2.88-2.82 (2H, m), 2.77-2.62 (3H, m). LCMS (ES+) 296.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[N:12]=[CH:13][C:14]([F:25])=[C:15]3[C:19]([C:20](=[O:24])[C:21](O)=[O:22])=[CH:18][NH:17][C:16]=23)[CH:7]=1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:57]1([C:63]2[C:67]([N:68]3[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]3)=[CH:66][NH:65][N:64]=2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C>[F:25][C:14]1[CH:13]=[N:12][C:11]([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:10][N:9]=2)=[C:16]2[NH:17][CH:18]=[C:19]([C:20](=[O:24])[C:21](=[O:22])[N:71]3[CH2:72][CH2:73][N:68]([C:67]4[C:63]([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)=[N:64][NH:65][CH:66]=4)[CH2:69][CH2:70]3)[C:15]=12
Reactant: c1ccc(-c2n[nH]cc2N2CCNCC2)cc1
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)O)c[nH]c23)n[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5c[nH]nc5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 48.8 %

Procedure:
To a solution of 2-(7-(5-(ethoxycarbonyl)-1H-pyrazol-3-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.017 g, 0.049 mmol) in DMF (1.5 mL) was added TBTU (0.017 g, 0.054 mmol), diisopropylethylamine (0.15 mL), and 1-(3-phenyl-1H-pyrazol-4-yl)piperazine (0.011 g, 0.049 mmol). The mixture was stirred under N2 at rt for 14.5 h and was quenched with 10 mL of H2O. The solvent was removed under reduced pressure, and the residue was dissolved in DMF. The DMF solution was passed though a plug of celite to remove solids, and the DMF solution was purified by prep HPLC to give the title compound as a white solid (13.3 mg). LCMS: m/e 557.4 (M+H)+, ret time 1.79 min (method 1). 1H NMR (500 MHz, MeOD) δ ppm 8.44 (s, 1H) 8.31 (d, J=2.44 Hz, 1H) 7.95 (d, J=7.32 Hz, 2H) 7.63 (s, 1H) 7.56 (s, 1H) 7.46 (t, J=7.63 Hz, 2H) 7.36 (t, J=7.48 Hz, 1H) 4.46 (q, J=7.22 Hz, 2H) 3.88-3.92 (m, 2H) 3.65-3.70 (m, 2H) 3.00-3.04 (m, 2H) 2.91-2.95 (m, 2H) 1.45 (t, J=7.02 Hz, 3H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[S:7][C:8]([CH:12]=O)=[C:9]([Cl:11])[N:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[S:7][C:8]([CH:12]2[O:4][CH2:1][CH2:2][O:3]2)=[C:9]([Cl:11])[N:10]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)c(C2OCCO2)s1
Yield: 96.2 %

Procedure:
Ethylene glycol (7.0 ml, 125.5 mmol) and p-toluenesulfonic acid monohydrate (0.56 g, 2.94 mmol) are added to a solution of 2,4-dichloro-thiazole-5-carboxaldehyde (7.88 g, 43.3 mmol) in toluene (100 ml). The reaction is heated at reflux and water removed via Dean-Stark for 4 h. The reaction is cooled, poured into 20% Na2CO3 (200 ml), and extracted with ethyl acetate (3×100 ml). The ethyl acetate is washed with aqueous saturated brine solution and dried over anhydrous Na2SO4. The solid is filtered off and the filtrate concentrated. The crude product is purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield (9.42 g, 96%) of 2,4-dichloro-5-([1,3]dioxolan-2-yl)-thiazole: 1H NMR (CDCl3): δ=6.07 (1H, s), 4.18-3.99 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Chloro-4′-hydroxybenzophenone (50 g, 0.215 mol) is dissolved in dichloromethane (400 ml). 3,4-Dihydro-2H-pyran (21.7 g, 0.257 mol) and a catalytic amount of p-toluenesulfonic acid are added to the solution. The solution is stirred for 6 hours at room temperature and then allowed to stand over night. 1 N aqueous sodium hydroxide solution (100 ml) is added to the reaction mixture and stirred for 15 minutes. Organic layer is separated and washed twice with 1 N aqueous sodium hydroxide solution and once with water. Dichloromethane solution is dried and evaporated to dryness. Yield 68.6 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1nncs1)OCc1ccccc1
Yield: 71.2 %

Procedure:
Using the same procedure as in Example 1(i), 10 g of N-benzyloxycarbonyl-L-phenylalanine, 3.3 g of triethylamine, 3.7 g of ethyl chlorocarbonate and 3.5 g of 2-amino-1,3,4-thiadiazole were reacted in chloroform to obtain 9.1 g (yield: 71%) of 2-(N-benzyloxycarbonyl-L-phenylalanylamino)-1,3,4-thiadiazole as white crystals of mp: 78°-83° C. and [α]D20 : +28.0° (C=1.2, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[C:26]=[O:27]>O1CCCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.30 mmol) produced in Example 12(v) was dissolved in tetrahydrofuran (10 ml), 1-isocyanato-4-(trifluoromethyl)benzene (84 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give the title compound (47 mg, 30%) as a yellow-brown powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:32]=[CH:31][N:30](OCC[Si](C)(C)C)[C:25]=4[N:26]=[C:27](C)[N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:32]=[CH:31][NH:30][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2ccn(OCC[Si](C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2cc[nH]c2n1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (13 mg, 0.023 mol) was stirred at room temperature in a solution of DCM (2 mL) containing TFA (1.5 mL) for two hours. The solvent was removed in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for one hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (9 mg, 90%).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)=[N:18][CH:19]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(Oc2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 110.6 %

Procedure:
To an N,N-dimethylformamide (100 mL) solution of 3-fluorophenol (3.30 g, 29.4 mmol) was added sodium hydride (1.41 g, 29.4 mmol, 50% in oil), which was stirred for 10 minutes at 0° C. 2,5-Dibromopyridine (4.64 g, 19.6 mmol) was then added to this mixture at 0° C., followed by 7 hours and 45 minutes of stirring at 110° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (5.81 g, quant.).
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1cc(F)cc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 3,5-difluorobenzeneboronic acid: MS (ESI) m/z 329 [M+H]+, 1H-NMR (CDCl3) δ 7.70-7.63 (1H, m), 7.55-7.33 (4H, m), 6.87-6.73 (2H, m), 3.89 (2H, t, J=6.2 Hz), 2.93 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.30 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:21][OH:22])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[O:29])(C)C.N1C=CC=CC=1>C1COCC1>[C:28]([O:22][N:21]=[C:17]([C:16]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12)[CH:18]([CH3:19])[CH3:20])(=[O:29])[NH2:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)C(=NO)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.6 %

Procedure:
To a solution of 783 mg (2.5 mmol) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hrs, followed by addition of 500 μl pyridine. After stirring for another 4 hours, the solvent was removed and the residue was extracted by ethyl acetate three times. The combined organic layers were washed with 1N HCl twice, brine and dried over MgSO4. After evaporation of the solvent under vacuum, 935 mg of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant furnished 621 mg (69.6%) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1026.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13]O.[O:15]1CCOC[CH2:16]1>>[CH3:13][O:7][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:1][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:15][CH3:16]
Reactant: C1COCCO1
Reactant: CO
Product: COCCOCCOCCOCCOC

Procedure:
In using the dioxane solvent of "H", it is preferred to develop first with dioxane alone, followed by a mixture of dioxane and alkanol and finished with alkanol alone (for example, dioxane/dioxane:methanol mixture/methanol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=2)=[O:14])[N:3]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Product: O=C(c1cccc(F)c1)c1nc(Cl)c2ccccc2n1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
To a suspension of ethyl 4-chloroquinazoline-2-carboxylate (237 mg, 1 mmol) in THF (5 mL) was added dropwise a 1M solution of 3-fluorophenylmagnesium bromide in THF (2 mL, 2 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 4 h. The mixture was quenched by adding 0.5 N HCl solution (5 mL) and the biphasic mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and dried over MgSO4. (4-chloroquinazolin-2-yl)(3-fluorophenyl)methanone was obtained as a yellow solid (190 mg, 66%). LC-MS (ESI) m/z 287 (M+H)+.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:22][CH2:23][CH3:24])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:22][CH2:23][CH3:24])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4-dimethyl-6-ethoxy-1-isopropyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-52, 0.180 g, 0.54 mmol), tetrapropylammonium perruthenate (0.027 g, 0.081 mmol) and 4-methylmorpholine N-oxide (0.158 g, 1.35 mmol) were reacted in acetonitrile (1.5 mL) and dichloromethane (7.5 mL) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:14][O:13][C:11]([C:10]1[CH:15]=[CH:16][C:7]([C:4]2[CH:5]=[CH:6][N+:1]([O-:25])=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1ccc(-c2ccncc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Methyl 4-(4-pyridyl)benzoate (1.49 g) was dissolved in dichloromethane (30 ml), 70% m-chloroperbenzoic acid (3.46 g) was added, and the mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium sulfite was added to conduct liquid separation. The resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound (1.33 g) as white powder.