Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CCC1c2ccccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CC1C=C([OH:9])C=CC=1C.[CH3:10][C:11]1[CH:12]=[C:13](O)[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:17])[C:16]=1[OH:9]
Reactant: Cc1cc(C)cc(O)c1
Reactant: Cc1ccc(O)cc1C
Product: Cc1cccc(C)c1O

Procedure:
3,4-dimethylphenol; 3,5-dimethylphenol;
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:8]=1.Cl.Cl.N1C2C(=NC=CC=2OC2C=CC(N[C:43]([NH:45][C:46](=[O:56])[CH2:47][C:48]3[C:53](Cl)=[CH:52][CH:51]=[CH:50][C:49]=3Cl)=[S:44])=CC=2F)C=C1.ClC1C=CC=C(Cl)C=1CC(N=C=S)=O.[N-]=C=S>>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:43]([NH:45][C:46](=[O:56])[CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[S:44])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reactant: Cn1ccnc1-c1cc2nccc(Nc3ccc(N)cc3)c2s1
Agent: Cl
Agent: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Agent: [N-]=C=S
Product: Cn1ccnc1-c1cc2nccc(Nc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)c2s1
Yield: 12 %

Procedure:
Starting from the compound 301, following the procedures described above for the synthesis of compound 269b (scheme 61, example 222) but replacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacethyl isothiocyanate, title compound 302 was obtained in 12% yield, as a yellow solid. 1H NMR (d-DMSO) δ (ppm): 12.47 (s, 1H), 11.76 (s, 1H), 10.83 (s, 1H), 8.41(d, 1H, J=6.9Hz), 7.84 (s, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.55(s, 1H), 7.46 (s, 1H), 7.43 (s, 1H), 7.32 (m, 4H), 7.28-7.20 (m, 1H), 7.20 (s, 1H), 6.94(d, 1H, J=6.8 Hz), 3.98 (s, 3H), 3.81 (s, 2H). MS (m/z): 499.1 (M+H) (found).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:35][CH3:36])=[C:10]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:24][CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:35][CH3:36])=[C:10]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:27]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C#CCCCO)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCO)cc1
Yield: 101.3 %

Procedure:
Pd(OH)2 (200 mg) was added to a solution of Intermediate 32 (200 mg, 0.40 mmol) in THF/MeOH (5 mL each). The solution was treated with H2 at ambient pressure for 3 h. The reaction mixture was then filtered through a plug of celite. The plug was washed with MeOH (50 mL) and the solvent was concentrated in vacuo to afford the title compound as a pale yellow solid (200 mg). ES/MS calcd. for C28H40N5O3+ 494.3. found m/z=494.4 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](C([Sn])=C(CCCC)CCCC)[CH2:25]CC>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.C1(C)C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:22]=[C:21]([CH:24]=[CH2:25])[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
0.54 g of tetrakis(triphenylphosphine)palladium (0) was added to 35 mL of toluene solution containing 3.5 g of tert-butyl 2-(benzamido)-4-bromobenzoate and 5.0 g of tributylvinyl tin, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane; ethyl acetate=20:1] to obtain 1.4 g of tert-butyl 2-(benzamido)-4-vinylbenzoate as white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)CC.NC[C@@H](O)[CH2:36][OH:37]>>[OH:37][CH2:36][C@H:2]([OH:1])[CH2:3][NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Reactant: NC[C@@H](O)CO
Product: CC(C)c1cnn2c(NCc3ccc(-c4ccccn4)cc3)nc(NC[C@@H](O)CO)nc12
Yield: 35 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 10 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of commercial (R)-3-amino-1,2-propanediol. Yield=35%. Oil. 1H NMR (300 MHz, CDCl3): δ 8.69 (d, 1H, J=4.5 Hz, Harom), 7.98 (d, 2H, J=8.3 Hz, Harom), 7.79-7.70 (m, 2H, Harom) 7.66 (s, 1H, Harom), 7.45 (d, 2H, J=8.3 Hz, Harom), 7.27.28-7.22 (m, 1H, Harom), 6.80 (bs, 1H, NB), 4.78 (d, 2H, J=5.8 Hz, CH2), 3.83-3.79 (m, 1H, CH), 3.65-3-3.55 (m, 4H, 2 CH2), 3.03 (hept, 1H, J=7.0 Hz, CH), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (BSI): m/z 434 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[N:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[N:3]1[CH2:20][CH:21]=C.[O:24]=[O+][O-].CSC>ClCCl>[O:1]=[S:2]1(=[O:23])[N:7]([CH:8]([CH3:9])[CH3:10])[CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[N:3]1[CH2:20][CH:21]=[O:24]
Reactant: O=[O+][O-]
Reactant: C=CCN1c2c(cccc2C(=O)OCC)CN(C(C)C)S1(=O)=O
Solvent: ClCCl
Solvent: CSC
Product: CCOC(=O)c1cccc2c1N(CC=O)S(=O)(=O)N(C(C)C)C2
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-8-carboxylate (1.1 g)(prepared from ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate and (prop-2-en-1-yl) bromide) was dissolved in dichloromethane (80 ml) and cooled to -75° C. Ozone was passed through the solution until the solution became blue. At which time, dimethyl sulfide (5 ml) was added and the solution allowed to come to room temperature over 1 hour. The solution was washed with water to remove the DMSO present, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a solid, ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate. This was dissolved in dichloroethane (50 ml) containing glacial acetic acid(5 drops) together with 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (0.8 g, 1.1 equiv.). Sodium triacetoxy borohydride (0.8 g, 1.1 equiv.) was added and the solution stirred overnight at room temperature. After washing with 2N sodium hydroxide (30 ml) and brine, the solution was dried, filtered and evacuated in vacuo to yield an off-white solid. Column chromatography eluting with ethyl acetate/hexane to ethyl acetate gave the required product, ethyl 3,4-dihydro-2,2-dioxo-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate, m.p. 95-97° C.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH:1]1([S:4]([N:7]2[CH2:8][CH:9]([O:11][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:10]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=S(=O)(C1CC1)N1CC(O)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC1CN(S(=O)(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
To a solution of 1-(cyclopropylsulfonyl)azetidin-3-ol (1.04 g, 5.87 mmol) and triethylamine (3.11 mL, 22.3 mmol) in tetrahydrofuran (20 mL) was added 4-dimethylaminopyridine (0.090 g, 0.73 mmol) followed by chlorotriethylsilane (1.00 M in THF, 8.0 mL, 8.0 mmol). The reaction was stirred at room temperature for 16 hours. To the reaction was added saturated sodium bicarbonate solution and the product was extracted with a 1:1 mix of ethyl acetate:hexanes three times. The combined organic extracts were washed with dilute HCl and brine, then dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient of 0-50% ethyl acetate in hexanes afforded desired product (1.0 g, 58%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].[NH2:12][CH:13]([CH2:39][CH2:40][CH:41]=[CH2:42])[C@@H:14]([OH:38])[C@@H:15]([N:23]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:24]([N:23]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:14]([CH:13]([NH:12][C:7](=[O:10])[CH:8]=[CH2:9])[CH2:39][CH2:40][CH:41]=[CH2:42])[OH:38])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=CCCC(N)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCCC(NC(=O)C=C)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Add sodium carbonate (0.324 g, 3.96 mmol) and acryloyl chloride (356 mg, 3.96 mmol) to a solution of (2S,3R)-4-Amino-2-dibenzylamino-1-phenyloct-7-en-3-ol (1.5 g, 3.6 mmol) in dichloromethane. Stir the reaction overnight. Concentrate under reduced pressure. Purify on silica gel with hexane/ethyl acetate mixtures to give a mixture of two products (0.8 g, 48%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:18](=O)[C@H:17]2[NH:20][C:21](=O)[C@@H:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2.C1COCC1.C(OCC)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][C@H:17]2[NH:20][CH2:21][C@@H:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2
Reactant: O=C1N[C@H]2CC=CC[C@@H]1N(c1ccc3ccccc3c1)C2=O
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: O=C1N[C@H]2C/C=C\C[C@@H]1N(c1ccc3ccccc3c1)C2=O
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Temperature: 120 °C

Procedure:
Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (0.8 g, 2.74 mmol) was dissolved in a solution of Dibal (THF, 1 M, 28 mL). The reaction was carried out in a large scale CEM microwave reaction vessel. The reaction mixture was heated to 120° C. for 0.5 h and then allowed to cool to room temperature. A one-liter Erlenmeyer flask was charged with diethyl ether (400 mL) and the reaction mixture was poured into the diethyl ether. A water solution of saturated Rochelle salts was added dropwise until gas stopped evolving and then water saturated with Rochelle salts (approximately 200 mL) was poured into the reaction mixture. The resulting mixture was stirred at room temperature until both phases were clear. The reaction mixture then was poured into a separatory funnel and the aqueous layer was discarded. The diethyl ether was dried with anhydrous magnesium sulfate and the solvent was removed using reduced pressure to yield a clear colorless oil.
Reaction SMILES: ClCCl.[Br:4][C:5]1[C:6]2[C:11]([C:12]3[CH2:17][N:16]([C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[OH:24])[C:15](=[O:25])[C:13]=3[CH:14]=1)=[N:10][CH2:9][CH2:8][CH:7]=2.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])(=O)=O>O>[Br:4][C:5]1[CH:14]=[C:13]2[C:15](=[O:25])[N:16]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[O:24][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:17][C:12]2=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1c2cc(Br)c3c(c2CN1[C@H]1CCCC[C@@H]1O)=NCCC=3
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1Cc2c(cc(Br)c3cccnc23)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 15 mL dichloromethane solution of 5-bromo-8-[(1S,2S)-2-hydroxycyclohexyl]-3,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (2.00 g, 5.54 mmol) at 0° C. was added 2,6 lutidine (1.29 mL, 11.1 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (1.91 mL, 8.30 mmol). The mixture was warmed to ambient temperature, and after 15 hr, diluted with water and extracted 2× with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The resultant white crystals were collected via filtration and washed with hexanes to provide 5-bromo-8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[C:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([OH:20])=[O:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)([OH:7])=[O:6]>>[C:2]([O:19][C:18]([C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([C:5]([O:7][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([CH2:15]3)[CH2:9]1)[CH2:11]2)=[O:20])([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C(C)C
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Product: CC(C)(C)OC(=O)C12CC3CC(C1)CC(C(=O)OC(C)(C)C)(C3)C2

Procedure:
In accordance with a conventional method in which isobutene is used under acidic conditions, 10 mmol of 1,3-dicarboxyadamantane was t-butoxylated to give 1,3-di(t-butoxycarbonyl)adamantane.
Reaction SMILES: [C:1]([C:9]1[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N:24]1([NH2:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[N:24]1([NH:30][C:15]([C:12]2[CH:13]=[N:14][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][CH:11]=2)=[O:17])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cnc(C(=O)c2ccccc2)nc1
Reactant: NN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCOCC1)c1cnc(C(=O)c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
2-Benzoyl-pyrimidine-5-carboxylic acid (50 mg, 0.22 mmol) is dissolved in anhydrous DCM (5 mL), and a 2 M oxalyl chloride (0.26 mmol, 0.13 mL) solution in DCM is added at rt followed by one drop of DMF. The mixture is stirred at rt for 2 h, and then concentrated in vacuo. The residue is dissolved in DCM (5 mL), and morpholine-4-ylamine (0.24 mmol, 25 mg) is added, followed by DIPEA (0.44 mmol, 57 mg). The reaction mixture is stirred at rt overnight, and then concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 10% MeOH in DCM to afford 2-benzoyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide (42 mg) as a solid. MS: 313 (M+H). IC50=342 nM.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[CH:29]1([C:32]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:16]=4)=[CH:6][N:5]3[CH:28]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)ccc2F)n(C)n1
Yield: 61.4 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (730 mg, 1.92 mmol) in N,N-dimethylacetamide (7 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (262 μL, 2.88 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-ethanol to give the title compound (529 mg, 61%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1cncc(Cl)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 3.63 g (20 mmol) sample of 3-chloro-5-trifluoromethylpyridine dissolved in 15 mL of DMF and cooled to 0° C. was added 960 mg of NaH (60%), 2.07 mL of benzyl alcohol was added slowly. The reaction mixture was stirred for 2 hours at 40° C. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and a brine solution. The organic layer was then dried over MgSO4. The resulting crude material was purified by flash chromatography on silica gel to give the title product. MS (DCI/NH3) m/e 154 (M+H)+. 1H NMR (CDCl3, 300 MHz) d: 8.56 (d, J=1.8 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H), 7.51 (dd, J=1, 0.9 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([CH:24]([C:27]([OH:29])=O)[O:25][CH3:26])[C:16]=2[F:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([CH:24]([C:27](=[O:29])[NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([C:32]#[N:31])=[CH:34][CH:35]=3)[O:25][CH3:26])[C:16]=2[F:30])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c(C(OC)C(=O)O)c1
Reactant: N#Cc1ccc(CN)cc1
Product: CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-4-[3-(Carboxy-methoxy-methyl)-5-ethoxy-2-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester was coupled with 4-aminomethyl benzonitrile to give (RS)-4-{3-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-5-ethoxy-2-fluoro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester according to general procedure B. Yellow oil. MS 564.4 ([M+Na]+)
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].[O-]Cl.[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1C
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-butyryl-4-(2-methylphenylamino)-8-(3-methylthiopropoxy)quinoline (0.33 g, 0.8 mmol) was dissolved in methylene chloride (15 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride: methanol 95:5 as the eluent gave 0.18 g (53%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:6])[CH3:2]>C1COCC1.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N)cc1
Reaction time: 24 h

Procedure:
A mixture of 2 (6.7 g, 1 mmol) in THF (100 ml) and EtOH (100 ml) is slowly added 10% Pd/C (680 mg) at room temperature. The reaction mixture is hydrogenated for 24 h with H2 balloon at room temperature. The mixture is filtered through celite pad and washed with EtOH. The filtrate is concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:31])[F:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:30])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:17]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
290 mg (purity 93%, 0.57 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoic acid (racemate) and 122 mg (0.63 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 195 mg (50% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.[F-:19].[Cs+].S1(CCCC1)(=O)=O.CCCCCC>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[F:19]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)C(F)F)cc(Cl)c1Cl
Agent: [Cs+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(OC(F)(F)C(F)F)cc(Cl)c1F
Temperature: 110 °C

Procedure:
3,4-Dichloro-5-nitro-(1',1',2',2'-tetrafluoroethoxy)-benzene (6.4 g) was added to a pre-dried solution of caesium fluoride (4.9 g) and sulpholane (70 ml). The stirred reaction mixture was then heated to 110° C. for a total of 27 hours. After allowing to cool to the ambient temperature, the reaction mixture was diluted with water and poured into hexane. The organic layer was water washed, dried over anhydrous magnesium sulphate, and the solvent removed by evaporation under reduced pressure to give 3-chloro-4-fluoro-5-nitro-(1',1',2', 2'-tetrafluoroethoxy)-benzene as an orange oil. 1H NMR δ(CDCl3): 7.85(1H,m), 7.62(1H,m), 5.95(1H,tt).