Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2Br)=[CH:3][CH:2]=1.[Li]CCCC.CCCCCC.[C:27]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)([O:29][CH2:30][CH3:31])=[O:28].Cl>CCCCCCC.C1COCC1>[OH:38][C:35]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:15])=[CH:2][CH:3]=2)[CH2:34][CH2:33][N:32]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:37][CH2:36]1
Reactant: Cc1ccc(Sc2ccccc2Br)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2Sc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a stirred reactor under nitrogen cover 2-(4-tolylsulfanyl)-phenyl bromide (600 g, 2.15 mol) was suspended in heptane (4.5 L). At room temperature 10M BuLi in hexane (235 mL, 2.36 mol) was added over 10 minutes. Only a small exotherm was noticed. The suspension was stirred for 1 hour at ambient temperature and then cooled down to −40° C. 1-Carbethoxy-4-piperidone (368 g, 2.15 mol) dissolved in THF (1.5 L) was added at a rate not faster than the reaction temperature was kept below −40° C. When the reaction has gone to completion, it was warmed to 0° C. and 1M HCl (1 L) was added keeping the temperature below 10° C. The acid aqueous phase was separated and extracted with ethyl acetate (1 L). The organic phases were combined and extracted with sodium chloride solution (15%, 1 L). The organic phase was dried over sodium sulphate and evaporated to a semi crystalline mass. It was slurried with ethyl ether (250 mL) and filtered off. Dried in an vacuum oven at 40° C. until constant weight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH:27][NH2:28])=[O:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:35](OC)(OC)(OC)[CH3:36].C1CCN2C(=NCCC2)CC1.C(O)(=O)C>C(O)CCC>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[O:26][C:35]([CH3:36])=[N:28][N:27]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(=O)NN)ccc2c1=O
Reactant: COC(C)(OC)OC
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: Cc1nnc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)o1
Yield: 90.1 %

Procedure:
A mixture of tert-butyl[6-(hydrazinocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.23 g, 0.50 mmol) and trimethyl orthoacetate (2.0 mL, 11 mmol) in 1-butanol (10 mL) was refluxed for 20 min. To the reaction mixture was added 1,8-diazabicyclo[5.4.0]-7-undecene (0.075 mL, 0.50 mmol), and then the mixture was refluxed for 1 h. The resulting reaction mixture was neutralized with acetic acid (0.040 mL, 0.70 mmol) and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and ethyl acetate (30 mL). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to give tert-butyl[2-isobutyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.22 g, 91%) as crystals.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:34][C:35]([CH3:42])([C:38]([F:41])([F:40])[F:39])[C:36]=1[CH3:37])#[N:31]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([CH3:42])([C:38]([F:41])([F:39])[F:40])[O:34][C:33](=[C:43]([C:44]#[N:45])[C:46]#[N:47])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
In 9 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 440 mg (1.12 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 310 mg (1.22 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 70° C. for 6 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 522 mg of a black powder (yield: 74.3%; mp: 205-207° C.)
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1C[C:46](O)=[O:47])(C)C.COC1C=CC=CC=1CC(O)=O>>[CH3:46][O:47][C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:31])[CH3:32])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: COc1ccccc1CC(=O)O
Product: COc1ccccc1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2-methoxyphenylacetic acid, mp 159°-161° C.
Reaction SMILES: [N:1]1[C:2]([CH:14]=O)=[N:3][N:4]2[CH:13]=[CH:12][C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=12.[Cl-].[CH3:17][C:18]1[N:23]2[N:24]=[C:25]([CH2:27][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C1COCC1.C(Cl)Cl>[CH3:17][C:18]1[N:23]2[N:24]=[C:25](/[CH:27]=[CH:14]/[C:2]3[N:1]=[C:5]4[C:6]5[CH:7]=[CH:8][CH:9]=[N:10][C:11]=5[CH:12]=[CH:13][N:4]4[N:3]=3)[N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1nc2c3cccnc3ccn2n1
Reactant: Cc1cccc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nn12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc2nc(/C=C/c3nc4c5cccnc5ccn4n3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of [1,2,4]triazolo[5,1-f][1,6]naphthyridine-2-carbaldehyde (20 mg, 0.1 mmol) in THF (1 mL) was added a solution of ((5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)triphenylphosphonium chloride (49 mg, 0.11 mmol) in DCM (3 mL), followed by the addition of DBU (45 mg, 0.3 mmol) at 0° C. under N2. The resulting mixture was stirred for 4 h at room temperature and diluted with DCM (15 mL). The mixture was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude residue, which was purified by prep. TLC to afford the title compound (17 mg, yield 52%). ESI MS: m/z 328 [M+H]+.
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]1([CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[O:5]1[C@@H:15]([CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:16]1[CH2:17][OH:18]
Reactant: OCC=CCCc1ccccc1
Reactant: CC(C)(C)OO
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1CCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a 1 L 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was added CH2Cl2 (350 mL), dried 4 Å molecular sieves (30 g) and L-(+)-diethyl tartrate (7.62 g, 0.037 mol). The resulting mixture was cooled to -20° C. and treated with Ti(O-i-Pr)4 (9.2 mL, 0.031 mol), followed by the addition of t-butylhydroperoxide (4.0 M in CH2Cl2, 182 mL, 0.78 mol) at a rate to maintain the temperature 2 -20° C. Upon complete addition, the reaction mixture was stirred for another 30 min, and then treated with a solution of the allylic alcohol (15) (50 g, 0.31 mol) in CH2Cl2 (30 mL) at a rate to maintain the temperature at -20° C. The reaction was stirred at the same temperature for 5 h, then filtered into a solution of ferrous sulfate heptahydrate (132 g) and tartaric acid (40 g) in water (400 mL) at 0° C. The mixture was stirred for 20 min, then transferred to a separatory funnel and extracted with t-BuOMe (2×200 mL). The combined organic phase was stirred with 30% NaOH solution containing NaCl, for 1 h at 0° C. The layers were again separated, and the aqueous phase extracted with t-BuOMe. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to yield the title compound (52.8 g) as an amber oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[C:8]([C:3]1([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:9]
Reactant: N#CC1(CO)CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CCCC2)cc1
Reaction time: 3 h

Procedure:
At 0° C., to a solution of 1-hydroxymethyl-cyclopentanecarbonitrile (10 g, 79.9 mmol) in CH2Cl2 (100 mL) was added pyridine (6.3 g, 79.9 mmol) and p-toluenesulfonyl chloride (12.18 g, 63.9 mmol). After stirred for 3 h, the solution was concentrated and the residue was used for next step reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Cl[C:32]([O:34][CH:35]1[CH:40]([C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])[CH2:39][CH2:38][CH:37]([CH3:50])[CH2:36]1)=[O:33].C1(C(C)(C)C2CCC(C)CC2O)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][C:13]=3[N:12]([C:32]([O:34][C@@H:35]3[CH2:36][C@H:37]([CH3:50])[CH2:38][CH2:39][C@H:40]3[C:41]([CH3:42])([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:43])=[O:33])[C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)Cl)C1
Reactant: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCS1(=O)=O)N2
Agent: CC(C)(C)[O-]
Agent: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2C3=C(C(=O)COC3)C(c3ccc(F)c(Br)c3)C3=C2CCS3(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the product from Example 11D (1.58 g, 3.7 mmol) in THF (40 mL) at 0° C. under a nitrogen atmosphere was added a 1M solution of potassium tert-butoxide in THF (4.1 mL) dropwise over 5 minutes. The mixture was stirred at ambient temperature for 30 minutes, cooled to 0° C., treated with a solution of 8-phenylmenthol chloroformate prepared from (−)-8-phenylmenthol as described in (Yamamoto, Y., J. Amer. Chem. Soc. (1992), 114, 121-125) (1.31 g, 4.4 mmol) in THF (20 mL) over 5 minutes, stirred at ambient temperature for 16 hours, diluted with methylene chloride (150 mL) and washed with aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography over silica gel (3:2:1 chloroform/hexanes/diethyl ether) to provide 0.98 g of the less polar diasteriomer.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C(#N)C.Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:14]([C:24]([O:26][CH3:27])=[O:25])=[C:13]([CH:28]([CH3:30])[CH3:29])[N:12]=1>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:14]([C:24]([O:26][CH3:27])=[O:25])=[C:13]([CH:28]([CH3:30])[CH3:29])[N:12]=[C:11]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[N:16]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Reactant: CNS(C)(=O)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 81.5 °C
Yield: 88.9 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 546 mg (5 mmol.) of N-methylmethanesulfonamide, 551 mg (5 mmol.) of sodium t-pentoxide, 10 mL of acetonitrile, and 309 mg (1 mmol.) of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine. The mixture was heated to 81-82° C. for 3 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 339 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine. The yield was 89% (based on the amount of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([OH:9])=[C:4](Cl)[N:3]=1.[F:11][C:12]([F:17])([F:16])[CH:13]1[CH2:15][O:14]1.C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[N:7]=[C:6]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[O:9][CH2:15][CH:13]([C:12]([F:17])([F:16])[F:11])[O:14][C:4]=2[N:3]=1
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Reactant: FC(F)(F)C1CO1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: FC(F)(F)C1COc2c(nc(Cl)nc2N2CCOCC2)O1
Temperature: 95 °C
Reaction time: 18 h
Yield: 33.9 %

Procedure:
A microwave vial was charged with 2,4,6-trichloro-pyrimidin-5-ol (200 mg, 1.00 mmol) and 2-trifluoromethyl-oxirane (429 μL, 5.01 mmol) then sealed. The reaction mixture was heated at 95° C. for 48 hours before being cooled and concentrated in vacuo. The resultant residue was dissolved into IMS (5 mL) then treated with triethylamine (198 μL, 1.42 mmol) and morpholine (83 μL, 0.95 mmol). The orange mixture was stirred for 18 hours at RT before being concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-20% ethyl acetate in cyclohexane) affording 2-Chloro-4-morpholin-4-yl-7-trifluoromethyl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (105 mg, 32%). LCMS: RT=3.20 min, [M+H]+=326/328.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.FC1C=CC([C@H](N)C)=CC=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Agent: C[C@@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Temperature: 140 °C
Yield: 28.9 %

Procedure:
A solution of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro nicotinonitrile (Method 1, 0.3 g, 1.0 mmol) and (R)-1-(4-fluorophenyl)ethanamine (0.3 g, 2.1 mmol) was added to n-BuOH (2 ml) and DIEA (0.18 g, 1.4 mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hours, then cooled to room temperature and concentrated. The resulting residue was purified by column chromatography (DCM-MeOH=80:1) to give the title compound (0.11 g, 26%). 1H NMR (400 MHz, CDCl3) δ 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.27 (d, J=9.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s, 1H), 5.24-5.20 (m, 2H), 1.87-1.83 (m, 1H), 1.60 (d, J=6.2 Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calcd.: 380. Found: [M+H]+ 381.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2ccccc2n1

Procedure:
Quinoline-2-carboxylic acid (Aldrich, 10.0 g, 57.7 mmol) was added to ethanol (500 mL) and sulfuric acid (25 mL) and refluxed for 7 hours. The mixture was concentrated under reduced pressure and dichloromethane (400 mL) was added. The organic layer was washed twice with saturated sodium bicarbonate (400 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (t, J=7.12 Hz, 3H), 4.43 (q, J=7.12 Hz, 2H), 7.76 (ddd, J=8.14, 6.95, 1.19 Hz, 1H), 7.88 (ddd, J=8.48, 6.95, 1.53 Hz, 1H), 8.11 (m, 2H), 8.18 (d, J=8.48 Hz, 1H), 8.58 (d, J=8.48 Hz, 1H). MS (DCI) m/z 202.05 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reaction time: 6 h
Yield: 98.5 %

Procedure:
Dissolve 4-bromo-2,6-dimethyl-phenol (20.1 g, 100 mmol) in DMF (250 mL) under nitrogen. Add cesium carbonate (48.9 g, 150 mmol) and benzyl bromide (13.1 mL, 110 mmol) and heat at 70° C. stirring mechanically for 6 h. Dilute with water (400 mL) and extract with 3/1 diethyl ether/hexanes (2×400 mL). Wash combined organics with brine (300 mL) and then dry (MgSO4), filter and concentrate in vacuo to give 28.67 g (99%) of the title compound as an oil which solidified on standing. 1H NMR(CDCl3): δ7.51-7.37 (m, 5H), 7.22 (s, 2H), 4.82 (s, 2H), 2.31 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)[CH:12]=2)=[CH:7][C:6]=1[F:35])=[O:4].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:37][OH:38])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)[CH:12]=2)=[CH:7][C:6]=1[F:35])=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)c2)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2cccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)c2)cc1F

Procedure:
In analogy to example 74, step 7, from 3-fluoro-3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4.4:1) as a white foam, MS (ESI+): m/z=483.2 ([M+H]+).
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>O.CN(C=O)C>[CH2:8]([O:12][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH2:9][CH2:10][CH3:11]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of NaH (270 mg/66% in oil) and THF (20 mL) was added n-butanol (1.1 mL) at 0° C., which was stirred for 45 minutes at room temperature. The reaction mixture was cooled to 0° C., and a mixture of 4-cyanobenzyl bromide (1.5 g) and THF (10 mL) was added by drops thereto at the same temperature. The reaction mixture was stirred for 3 hours at room temperature, after which DMF (10 mL) was added to the reaction mixture, which was stirred for 4.5 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with saturated brine, after which the solvent was evaporated from the organic layer under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:6) to obtain the titled compound (1.2 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[C:6]([Cl:17])[N:5]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[Cl:17][C:6]1[CH:7]=[C:8]([N:10]([CH3:18])[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:9]=[C:4]([Cl:3])[N:5]=1
Reactant: Clc1cc(Nc2cncnc2)cc(Cl)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
NaH (103 mg, 4.29 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (9.5 mL) was added. The slurry was cooled to 0° C. and compound 13 (938 mg, 3.89 mmol, 1.00 eq) was added as a solution in THF (9.5 mL). After stirring at 0° C. for 30 minutes methyl iodide (267 μL, 4.29 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 920 mg (93%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.87 (s, 2H), 6.77 (s, 2H), 3.36 (s, 3H); [M+1]+: 255.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.CCOCC.[Mg].Cl[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C1CCCCC1Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C1CCCCC1c1ccc(F)cc1
Reaction time: 18 h

Procedure:
The Grignard reagent prepared by adding 210 g of p-fluorobromobenzene in 800 ml. of anhydrous ether to 29.1 g of magnesium turnings in 50 ml. of ether was added, with cooling to keep the temperature of the reaction less than 15° C., to a solution of 158.4 g of 2-chlorocyclohexanone in 800 ml. of anhydrous benzene. The reaction was stirred at 25° for 18 hrs. then the ether was distilled off and the resulting benzene solution refluxed for 24 hrs. It was then poured into a mixture of 1 liter water and 200 ml. hydrochloric acid and extracted with ether. After evaporation of the ether the residue was distilled to yield 117 g (51%), b.p. 115 (0.2 mm). The material solidified on standing and was recrystallized from hexane, m.p. 56°-59° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4ncsc4cc32)CC1

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (35 mg, 0.74 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32 mg, 0.18 mmol) and