Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=3)[C:16]=2[CH:34]=1.CC(C1C=C(C(C)C)C(S([N:50]=[N+:51]=[N-:52])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:50]([CH:19]1[N:18]=[C:17]([C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=2)[C:16]2[CH:34]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:51]=[N-:52]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: COc1ncc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ncc(C2=NC(N=[N+]=[N-])C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Yield: 94.7 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (7.0 mL of 0.5 M in toluene, 3.5 mmol), 7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.16 g, 3.35 mmol), trisyl azide (2.60 g, 8.40 mmol) and acetic acid (0.85 mL, 14.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (2:3 hexanes:EtOAc) provided the title compound as a pale yellow solid (1.23 g, 95%). 1H-NMR (CDCl3): δ 8.64 (s, 1H), 7.54 (dd, J=2.3 Hz, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 4.51 (s, 1H), 4.08 (s, 3H), 3.78 (s, 3H), 3.47 (s, 3H). MS (ESI) (M+H)+388.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[C:17]([Cl:23])[CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26]>>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:25][OH:26])=[C:17]([Cl:23])[CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)c(Cl)c2)cc1
Reactant: NO
Agent: Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=NO)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 4′-{[tert-butyl(dimethyl)silyl]oxy}-3-chloro-1,1′-biphenyl-4-carbaldehyde (405 mg, 1.17 mmol) with hydroxylamine hydrochloride (154 mg, 2.22 mmol) according to Method C to yield a yellowish oil which was used in the next step without purification: MS (ESI) m/z 362/364 (M+H)+.
Reaction SMILES: [NH:1]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:2]([C:6]([N:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C@H:2]([C:6]([N:8]1[CH2:33][CH2:32][CH2:31][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of Z-Val-Pro-Val-Pro-OtBu [SEQ ID No: 9] (1.1 mmol) was treated with trifluoroacetic acid (2.76 mL, 3.58 mmol) in dichloromethane (4.85 mL), the reaction was stirred at room temperature for 3 h. Then, the solution was evaporated to dryness and the residue was lyophilized to give Y (84% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=O)[NH:4][C:3]=1[CH3:15].O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([Cl:18])=[N:4][C:3]=1[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(C)c(Br)c2c1
Product: COc1ccc2c(Cl)nc(C)c(Br)c2c1
Temperature: 25 °C

Procedure:
A suspension of 4-bromo-6-methoxy-3-methyl-2H-isoquinolin-1-one (9.3 g, 35 mmol) in POCl3 (50 ml) is refluxed for 1 h. After cooling to room temperature, POCl3 is removed. The residue is diluted with water (50 ml) and neutralized with saturated NaHCO3. The resulting solid is filtered and dried to give 9.8 g of 4-bromo-1-chloro-6-methoxy-3-methyl-isoquinoline. 1H NMR (CDCl3) 8.17 (d, 1H), 7.43 (s, 1H), 7.25 (d, 1H), 4.01 (s, 3H), 2.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[CH:30][C:29]=2[CH:40]=1>CCOCC>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]([CH:37]([CH3:38])[CH3:39])[C:34]([O:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:4]=3)=[O:35])=[CH:30][C:29]=2[CH:40]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1ccc(F)c(Oc2ccccc2)c1)c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-fluoro-3-phenoxybenzyl alcohol (0.22 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for about 1 hour and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography, gives 4-fluoro-3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11](OC)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Br
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Br)cc1

Procedure:
2-Benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579–1582) was converted to the 5-hydroxy-analog according to the method of Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy-analog according to the method of Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method of Example 9, provided 2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-methylphenylboronic acid according to the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide was oxidized to the title compound according to the method of Example 10 (yield: 210 mg, 98%). mp 154–156° C. 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 3.07 (s, 3H), 4.89 (q, J=9 Hz, 2H), 7.08 (s, 4H), 7.37 (d, J=9 Hz, 2H), 7.88 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 423 (M+H)+. Anal. calc. for C20H17F3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.59; H, 4.11; N, 6.53.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2cccc(F)c2)CC1
Temperature: 20 °C
Yield: 37.6 %

Procedure:
The experiment is carried out as in Example 1, starting with 2(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide(8.4 g), triethylamine (4.2 cc) and 4-(3-fluorophenyl)piperazine (5.3 g) in toluene (100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and ethyl acetate (5-50 vol) as eluant, and recrystallization from boiling acetonitrile (20 cc), 2-(3-[4-(3-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (4.7 g) is obtained, m.p. 103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH3:27])[C:10]=1[C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22]C)=[C:15]([CH:24]([CH3:26])[CH3:25])[CH:14]=1)=[O:12].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:28])=[C:9]([CH3:27])[C:10]=1[C:11]([C:13]1[CH:14]=[C:15]([CH:24]([CH3:26])[CH3:25])[C:16]([OH:22])=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:18]=1)=[O:12]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3cccc(Br)c3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2cccc(Br)c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 76.2 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(3-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.34 g, 2.78 mmol) and 1M boron tribromide/CH2Cl2 (5.84 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetonelhexane gave 0.995 g (73%) of the title compound. 1H NMR (DMSO-d6) δ1.14 (d, 12 H), 1.80 (s, 3 H), 2.19 (s, 3 H), 3.32 (septet, 2 H), 3.87 (s, 2 H), 7.09 (d, 1 H), 7.22 (t, 1 H), 7.26 (s, 1H), 7.39 (d, 1 H), 7.43 (s, 2 H), 9.13 (s, 1 H). IR (KBr) 3350, 2950, 1580, 1560 and 1325 cm−1. mass spectrum (EI) m/z 468 (M+). Anal. Calcd. for C26H29BrO3: C, 66.53; H, 6.23; N, 0.00. Found: C, 66.50; H, 6.22; N, 0.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:13][CH:12]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH+:8]([O-:37])[C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(C)Oc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(C(=O)[NH+]([O-])c2c(Cl)cncc2Cl)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A suspension of N-(3,5-dichloropyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide (60 mg, 0.144 mmol) (example 32) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.722 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 30% acetone-chloroform as the eluent to give 57 mg of N-(3,5dichlorpyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 247-248° C.
Reaction SMILES: C([C:4](=[C:23]1[S:27][CH:26]=[CH:25][S:24]1)[C:5]([NH:7][CH:8]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6])(O)=O>O1CCOCC1>[CH2:20]([N:16]([CH2:17][CH2:18][CH3:19])[C:14](=[O:15])[CH:8]([NH:7][C:5](=[O:6])[CH:4]=[C:23]1[S:27][CH:26]=[CH:25][S:24]1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(=O)C(CCC(=O)O)NC(=O)C(C(=O)O)=C1SC=CS1
Solvent: C1COCCO1
Product: CCCN(CCC)C(=O)C(CCC(=O)O)NC(=O)C=C1SC=CS1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Dioxane (1.5 l) and activated carbon (10 g) were added to the 4-((2-carboxy-2-(1,3-dithiol-2-ylidene)acetyl)amino)-5-(dipropylamino)-5-oxopentanoic acid (6) obtained in Synthesis Example 4. The resulting mixture was stirred at 50° C. for 30 minutes. The activated carbon was filtered off, and the solvent was removed from the filtrate under reduced pressure. Acetone was added to the thus-obtained residue. The resulting crystals were collected by filtration, washed with water, acetone and diethyl ether, and then dried at 60° C. for 8 hours under reduced pressure, whereby 5-(dipropylamino)-4-((2-(1,3-dithiol-2-ylidene)acetyl)amino)-5-oxopentanoic acid (1) (67 g, yield: 72% (based on the compound (5)) was obtained as pale yellow crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH2:2]1.[CH2:16]=[CH:17][CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[CH:10]1[C:5]2[C:4]3([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH:17]=[CH:18][CH2:19][CH:3]3[CH2:2][O:1][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC=C
Reactant: CCOC(=O)C1=CCOc2ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C12CC=CCC1COc1ccccc12
Temperature: 150 °C
Yield: 39.3 %

Procedure:
A solution of the product of Example 15 (20.3 g) was dissolved in toluene (100 ml) and to it was added BHT (0.5 g) and butadiene (73 g) the reaction vessal was pressurized with nitrogen (1900 psi) and heated to 150° C. for 6 days. The resulting syrup (40 g) was partitioned between heptane and acetonitrile. The acetonitrile solution was washed with fresh heptane then evaporated in vacuo. The heptane phase was extracted with fresh acetonitrile which was evaporated to give a further recovery of crude product. The resulting oils were chromatographed on silical gel (eluting with ethyl acetate:heptane (1:60)), to give the title compound as a crystalline solid (10.1 g, 38%), mp 88° C. ##STR26##
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[C:3](=[O:25])[N:4]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2C(=O)C(Nc3ccc(OC)cc3)=C(c3ccccc3)C2=O)cc1
Temperature: 150 °C
Yield: 30.1 %

Procedure:
Methyl 4-[(3-chloro-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]benzoate (0.24 mmol, 85 mg), 4-methoxyaniline (0.26 mmol, 33 mg) and triethylamine (0.29 mmol, 29 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 32 mg (30%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.03-7.99 (m, 2H), 7.52-7.46 (m, 2H), 7.21 (bs, 1H), 7.16-7.05 (m, 3H), 7.01-6.95 (m, 2H), 6.62-6.52 (m, 4H), 4.81 (s, 2), 3.90 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[N:6][CH:7]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[CH3:14][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH2:8][O:9][CH3:10])[N:4]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COCc1ncc(Br)c(C(=O)O)n1
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: COCc1ncc(Br)c(C(=O)OC)n1
Yield: 26.5 %

Procedure:
To a solution of 5-bromo-2-methoxymethyl-pyrimidine-4-carboxylic acid (2.5 g, 10.1 mmol) in acetone (100 ml) was added Cs2CO3 (19.8 g, 60.7 mmol) followed by methyliodide (3.8 ml, 60.7 mmol). The mixture was heated to reflux for 8 h. The reaction mixture was then filtered, and the filtrate was evaporated. The crude material was purified by silica gel chromatography using a ethyl acetate/hexane eluent to yield 700 mg (27%) of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:32].[O:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:39][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:32]
Reactant: Cn1cc(C(c2ccc(Cl)c(F)c2)n2ccc(-c3ccnc(S(C)(=O)=O)n3)cc2=O)cn1
Reactant: NC1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cn1cc(C(c2ccc(Cl)c(F)c2)n2ccc(-c3ccnc(NC4CCOCC4)n3)cc2=O)cn1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
1-((4-Chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (343 mg, 0.724 mmol) as a solution in DMA (5 mL) was added to a microwave tube equipped with a stir bar. Tetrahydro-2H-pyran-4-amine (366 mg, 3.62 mmol) was then added neat by syringe. The solution was heated in a microwave apparatus with stirring to 120° C. for 1 hour. After 1 hour, the solution was diluted to 30 mL with ethyl acetate and washed with a water/brine mixture (4×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. TLC in 5/95 methanol/ethyl acetate showed complete loss of starting material and a new spot of nearly the same rf. The crude product was loaded onto a Biotage 40S column with 2.5/97.5 methanol/ethyl acetate and eluted. Product containing fractions were pooled and concentrated to a foam, 1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (225 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 8.39 (d, 1H), 7.37 (m, 4H), 7.23 (s, 1H), 7.18 (br s, 1H), 7.00 (m, 2H), 6.90 (d, 1H), 6.79 (dd, 1H), 5.15 (br d, 1H), 4.11 (m, 1H), 4.00 (m, 2H), 3.91 (s, 3H), 3.56 (m, 2H), 2.06 (m, 2H), 1.57 (m, 2H); m/z (APCI-pos) M+1=496.1.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][C:6]1[O:7][C:8]([CH3:14])=[C:9]([C:11](O)=[O:12])[N:10]=1.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][C:6]1[O:7][C:8]([CH3:14])=[C:9]([CH2:11][OH:12])[N:10]=1
Reactant: Cc1oc(C=Cc2ccccc2Cl)nc1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1oc(C=Cc2ccccc2Cl)nc1CO

Procedure:
A mixture of 2-(2-chlorostyryl)-5-methyl-4-oxazolecarboxylic acid (4.8 g) and thionyl chloride (24 ml) was refluxed with stirring for an hour. The thionyl chloride was distilled off and the crystalline residue (acid chloride) was washed with isopropyl ether and dissolved in dimethoxyethane (20 ml). The solution was added dropwise to a suspension of sodium borohydride (1.4 g) in dimethoxyethane (30 ml) with ice-cooling and stirring. The reaction was allowed to proceed under ice-cooling for 30 minutes and the reaction mixture was adjusted to pH 2 with 2N hydrochloric acid and refluxed for 30 minutes. The solvent was then distilled off and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting crystalline precipitate was collected by filtration and washed with isopropyl ether to give 2-(2-chlorostyryl)-4-hydroxymethyl-5-methyloxazole; yield 3.9 g (85.9%). Recrystallization from ethanol gave colorless needles melting at 122°-123° C.
Reaction SMILES: [F:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:23])[CH2:21][CH3:22].Cl>C(=S)=S>[C:20]([C:10]1[CH:9]=[CH:8][C:7]2[C:6]3[C:14](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:13][C:12]=2[C:11]=1[F:15])(=[O:23])[CH2:21][CH3:22]
Reactant: Fc1cccc2c1Cc1c(F)cccc1-2
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc2c(c1F)Cc1c(F)cccc1-2
Reaction time: 2 h
Yield: 31.8 %

Procedure:
50.5 g of 1,8-difluorofluorene (K-1) was dissolved in 150 ml of carbon disulfide, and the temperature was lowered to −10° C. With the temperature maintained at this level, 30 g of anhydrous aluminum chloride was added, and with the temperature still held at −10° C., 25.4 g of propionyl chloride was added dropwise over a period of 30 minutes, and the mixture was then stirred at the same temperature for 2 hours. Following completion of the stirring, the reaction mixture was poured into 200 ml of cooled 1N dilute hydrochloric acid, and was then extracted with 250 ml of toluene. The thus obtained organic layer was washed twice with 100 ml portions of water. Following drying, the solvent was removed by evaporation and the product purified by silica gel chromatography (toluene) to yield 20.5 g of 2-propionyl-1,8-difluorofluorene (K-2).
Reaction SMILES: [Si](OC[C:20]1([C:36]#[N:37])[CH2:24][CH:23]=[CH:22][N:21]1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:56]1CCC[CH2:57]1>>[CH2:34]([O:33][C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:21]2[C:22]([CH2:57][OH:56])=[CH:23][CH:24]=[C:20]2[C:36]#[N:37])=[CH:30][CH:29]=1)=[O:32])[CH3:35]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(N2C=CCC2(C#N)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)c1ccc(-n2c(C#N)ccc2CO)cc1

Procedure:
To a solution of 2-tert-butyldiphenylsilyloxymethyl-1-(4-ethoxycarbonylphenyl)pyrrole-2-carbonitrile (1.9 g) in tetrahydrofuran (19 ml) was added tetrabutylammonium fluoride (5.6 ml, 1M tetrahydrofuran solution) through syringe at ambient temperature. The mixture was stirred for half an hour at the same temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with aqueous hydrochloric acid, water and brine, and then dried, and concentrated in vacuo. The oily residue was chromatographed on silica gel (elution by ethyl acetate/n-hexane =1/1) to give 1-(4-ethoxycarbonylphenyl)-5-hydroxymethylpyrrole-2-carbonitrile (702.5 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:23]1[CH2:24][CH2:25][C:26]([F:30])([F:29])[CH2:27][CH2:28]1)[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:6]
Reactant: COc1ccc(C(CN)N2CCC(F)(F)CC2)cc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: COc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cc1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.