Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].P(Br)(Br)[Br:18]>CCOCC>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:2][Br:18]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Yield: 215.5 %

Procedure:
A solution of 1.00 g (4.5 mmol) of (E,E)-farnesol (Aldrich, further purified by flash chromatography) in 10 ml of distilled ether at 0° C. under argon in the dark was treated dropwise with a solution of 195 μL (2.05 mmol, 0.45 eq.) of PBr3 in 2 ml of ether. The resultant mixture was stirred at 0° C. for one hour, then quenched with water and separated. The organic phase was washed with 5 ml of H2O, 5 ml of saturated NaHCO3, and 5 ml of brine, dried over Na2SO4 and evaporated to give 1.26 g (98%) of crude bromide as a clear oil. TLC Silica (2:8 ethyl acetate:Hexane) Rf=0.69.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][CH2:22]3)[N:18]=[C:17]([O:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:16]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH2:49])([CH3:46])[CH3:45]>>[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH:49][C:32](=[O:33])[CH2:31][CH2:30][O:29][C:17]1[C:16]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][CH2:22]2)[N:18]=1)([CH3:46])[CH3:45]
Reactant: CC(C)c1ccccc1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCCN(C)CC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCCN(C)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(4-methylhomopiperazinyl)-4-pyrimidinyloxy]propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [C:1](O)(=O)C.[Cl:5][C:6]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:7]=1[CH2:8][C:9]1[C:10]([CH3:25])=[N:11][N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[NH:14][C:13]=12.[CH3:31][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Cl:5][C:6]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:7]=1[CH2:8][C:9]1[C:13]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:16][C:17](=[O:18])[N:12]2[N:11]([CH3:1])[C:10]=1[CH3:25].[Cl:5][C:6]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:7]=1[CH2:8][C:9]1[C:10]([CH3:25])=[N:11][N:12]2[C:17]([O:18][CH3:31])=[CH:16][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:14][C:13]=12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)O
Reactant: Cc1nn2c(=O)cc(-c3ccncc3)[nH]c2c1Cc1cccc(Cl)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-c2ccncc2)nc2c(Cc3cccc(Cl)c3Cl)c(C)nn12
Product: Cc1c(Cc2cccc(Cl)c2Cl)c2nc(-c3ccncc3)cc(=O)n2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %
Yield: 40 %

Procedure:
To a solution of 3-(2,3-dichlorobenzyl)-2-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one acetate (600 mg, 1.347 mmol) in dichloromethane/methanol (30 mL/15 mL) was added trimethylsilyldiazomethane (2 mL, 4.04 mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by a silica gel chromatography to give 3-(2,3-dichlorobenzyl)-1,2-dimethyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(1H)-one (214 mg, 40%) and 3-(2,3-dichlorobenzyl)-7-methoxy-2-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (83 mg, 15%). The structures of the two products were assigned according to NOESY. Example 33: 3-(2,3-dichlorobenzyl)-1,2-dimethyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(1H)-one: LC/MS: MS (ES+) m/e 399 (MH+); 1H NMR (300 MHz, DMSO-d6) □ ppm 2.42 (s, 3H), 4.15 (s, 2H), 4.21 (s, 3H), 6.59 (s, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.36 (dd, J=1.8, 7.8 Hz, 1H), 7.51 (dd, J=1.8, 7.8 Hz, 1H), 7.95 (d, J=6.3 Hz, 2H), 8.66 (d, J=6.3 Hz, 2H). Example 34: 3-(2,3-dichlorobenzyl)-7-methoxy-2-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine: LC/MS: MS (ES+); 1H NMR (300 MHz, CDCl3) δ ppm 2.44 (s, 3H), 4.31 (s, 5H), 6.58 (s, 1H), 7.04-7.07 (m, 2H), 7.32 (dd, J=3.0, 6.6 Hz, 1H), 7.50 (dd, J=1.5, 4.5 Hz, 2H), 8.76 (dd, J=1.5, 4.5 Hz, 2H).
Reaction SMILES: [N:1]1([C@@H:10]([C@@H:13]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[O:14][CH2:15][CH2:16][F:17])[CH2:11][OH:12])[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([O:23][CH2:22][C@@H:20]([OH:21])[C@@H:18]([OH:19])[C@@H:13]([O:14][CH2:15][CH2:16][F:17])[C@H:10]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH2:11][OH:12])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:29]2[CH:46]=[CH:47][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn([C@H](CO)[C@H](OCCF)[C@H](O)[C@H](O)CO)c(=O)[nH]c1=O
Product: COc1ccc(C(OC[C@@H](O)[C@@H](O)[C@@H](OCCF)[C@@H](CO)n2cc(C)c(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
Compound 5 (4.07 g, 12.79 mmol) was mixed with 4,4′-dimethoxytrityl chloride (4.56 g, 13.46 mmol) and dried over P2O5 under reduced pressure. The residue was dissolved in anhydrous pyridine (43 mL) and stirred at room temperature for 6 hours under an atmosphere of argon. The mixture was quenched with methanol (3 mL). The reaction mixture was diluted with EtOAc (200 mL), washed with aqueous NaHCO3 (saturated, 300 mL) and brine (200 mL) then dried over Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel column chromatography (eluted first with 70% EtOAc in hexanes and then increasing the polarity) to yield Compound 6 (7.1 g, 89%). ES MS m/z 643.2 [M+Na]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])=[CH:20][C:19]=3[Cl:33])[CH:11]=2)[CH:9]=1)=[O:4].O.[Li+].[OH-].CCOC(C)=O>CO.Cl>[Cl:33][C:19]1[CH:20]=[C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:22]=[CH:23][C:18]=1[C:17]([C:12]1[CH:11]=[C:10]([N:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7]2)[CH:15]=[CH:14][C:13]=1[CH3:16])=[O:34]
Reactant: COC(=O)c1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2cc(C(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
A suspension of compound 132 (100 mg, 0.21 mmol) in MeOH (5.0 mL) was added H2O (0.6 mL) and LiOH (25 mg, 1.0 mmol) and the resulting reaction mixture was refluxed for 1 h. EtOAc was added to the reaction and pH adjuste to 1-2 with concentrated HCl (37%, 6 drops). The organic phase was separated and the aqueous layer was extracted with more EtOAc. The organic phases were collected and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to give the title compound as white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29]O.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.C1COCC1.O>[Cl:23][C:17]1[CH:18]=[C:19]([O:22][CH2:29][CH2:28][CH2:27][O:26][CH3:25])[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH:5]([CH2:4][C:3]([OH:2])=[O:24])[CH2:6][O:7][C:8]=2[CH:13]=1
Reactant: COCCCO
Reactant: COC(=O)CC1COc2cc(OCc3ccc(O)cc3Cl)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1ccc(COc2ccc3c(c2)OCC3CC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To the solution of methyl(6-((2-chloro-4-hydroxybenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetate (34.9 mg) in toluene (0.25 mL) and THF (0.25 mL) were added a solution of 3-methoxy-1-propanol (13.5 mg) in toluene (0.5 mL) and a solution of tributylphosphine (40.5 mg) in toluene (0.5 mL). To the mixture was added ADDP (50.5 mg) and the mixture was stirred at room temperature overnight. To the mixture was added water (1.0 mL), and the mixture was extracted with EtOAc (2.0 mL). The organic layer was separated and concentrated. The residue was purified by preparative HPLC (C18, eluent: water/CH3CN (including 0.1% TFA)). After solvent evaporated, the residue was added 1.0 N NaOH (0.5 mL) and the mixture was stirred at 50° C. overnight. The mixture was added EtOAc (3.0 mL), and the organic layer was separated. The aqueous layer was acidified with 10% aqueous citric acid solution (0.5 mL), and extracted with EtOAc (3.0 mL). The organic layer was separated and concentrated. The residue was purified by preparative HPLC (C18, eluent: water/CH3CN (including 0.1% TFA)). The solvent was evaporated to give the title compound (13.1 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 34.9 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added methanesulfonyl chloride (0.0064 g, 0.0043 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 38 minutes. The reaction was diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid, which was purified by chromatography on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (8.3 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 3.10 (s, 3 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=8.82, 2.57 Hz, 1 H) 7.64 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.60, 1.65 Hz, 1 H) 10.29 (s, 1 H) 14.17 (s, 1 H). MS (ESI−) m/z 504 (M−H)−.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[C:15]1([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:22]=[CH:23][C:24]([C:25]([N:8]2[CH2:9][C:10]3[N:4]([CH:3]=[CH:2][CH:1]=3)[CH2:5][C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]2=3)=[O:26])=[CH:28][CH:29]=1
Reactant: c1cnc2c(c1)NCc1cccn1C2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2Cc2ncccc21

Procedure:
A stirred mixture of 9,10-dihydro-4H-3a, 5,9-triaza-benzo[f]azulene of Step D (0.54 mmol), 4-phenylbenzoylchloride (1.08 mmol) and triethylamine (1.08 mmol) in toluene was refluxed under nitrogen for 72 hours. The reaction was cooled and the solvent removed in vacuo. Chromatography of the residue over silica gel Merck-60 with a solvent gradient from 5 to 20% ethyl acetate in hexane provided the title compound as a tan solid.
Reaction SMILES: C([N:5]1[C:9](=O)[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6]1)CCC.N#C[Br:16]>ClCCl>[Br:16][C:9]1[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6][N:5]=1
Reactant: CCCCn1sc2nccn2c1=O
Reactant: N#CBr
Solvent: ClCCl
Product: Brc1nsc2nccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a cooled solution of 2-butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one (4.78 g, 0.0242 mole) in 25 mL dichloromethane, cyanogen bromide (5.13 g, 0.0482 mole) was added in one portion and the mixture was stirred for 16 h at room temperature. The precipitate was filtered, slurried in 10 mL of methanol and subsequently washed with dichloromethane to give 4.45 g (90%) of 3-bromoimidazo[1,2-d]-1,2,4-thiadiazole as a colourless powder: mp 220° C. (dec); MS m/z 205, 203 (M+). Anal. Calcd for C4 H2N3SBr.1/2 H2O: C, 22.55; H, 1.42; N, 19.72; O, 3.75; S, 15.02; Br, 37.50. Found: C, 22.79; H, 1.41; N, 19.42; O, 2.67; S, 14.61; Br, 38.20.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](SC)=[N:13][C:12]=3[CH:18]=2)=[N:6][NH:5][C:4](=[O:19])[CH2:3]1.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>O>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[N:13][C:12]=3[CH:18]=2)=[N:6][NH:5][C:4](=[O:19])[CH2:3]1
Reactant: NCCCCN
Reactant: CSc1nc2cc(C3=NNC(=O)CC3C)ccc2o1
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2oc(NCCCCN)nc2c1
Reaction time: 0.5 h

Procedure:
4.1 g (15.0 mmol) of 5-methyl-6-(2-methylthiobenzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and 15 ml of 1,4-diaminobutane are heated to 60° C. for 45 minutes, then stirred into 200 ml of water and left to crystallise at ambient temperature. After about 30 minutes the product is suction filtered, washed with about 50 ml of water and dried at 60° C. in a circulating air dryer.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25].N1CCCCC1>C(O)C>[O:25]=[C:17]1[NH:16][C:24]2[C:19](/[C:18]/1=[CH:1]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)C=Cc1ccccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)CCc1ccccc1/C=C1/C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of 1 g of ethyl 3-(2-formylphenyl)propenate, 500 mg oxindole and 0.1 mL piperidine in 5 mL of ethanol was stirred at 90° C. overnight. The mixture was evaporated and purified on a silica gel column to give 450 mg of ethyl (E)-3-[(2-oxo-1,2-dihydroindol-3-ylidenemethyl)phenyl]propionate (M+1=322).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
Palladium (II) acetate (0.15 g, 0.67 mmol) was added to a stirred solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6 g, 30 mmol) and 4-iodo-N-2-pyridinylbenzenesulfonamide (10.8 g, 30 mmol) in dimethylacetamide (40 ml) and tributylamine (10 ml, 42 mmol) at 95° C. After 100 min. the solution was filtered and evaporated at 50°-60° C. (bath temp.) until solid material appeared. The mixture was diluted with isopropanol (0.5 l) and chilled in a freezer. The product was filtered off to yield 7.1g (52%).
Reaction SMILES: [F:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([O:38][CH:39]=[CH2:40])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:43]([F:46])([F:45])[F:44].[Zn](CC)[CH2:48]C.C(I)I>C1(C)C=CC=CC=1>[CH:39]1([O:38][C:33]2[CH:32]=[C:31]([C@@:9]([NH:8][C:6](=[O:7])[C:5]3[CH:41]=[CH:42][C:2]([F:1])=[C:3]([C:43]([F:46])([F:45])[F:44])[CH:4]=3)([C:17]3[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=3)[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:36]=[CH:35][C:34]=2[F:37])[CH2:48][CH2:40]1
Reactant: CC[Zn]CC
Reactant: C=COc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: ICI
Solvent: Cc1ccccc1
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC2CC2)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of (R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (66 mg, 0.10 mmol) in 0.5 ml toluene was added Et2Zn (1 N, 0.2 ml, 0.2 mmol), followed by CH2I2 (16 ml, 0.2 mmol). The reaction mixture was stirred at 120° C. for 3 h. The reaction mixture was quenched by addition of 1 N HCl and the aqueous layer was extracted with CH2Cl2. The organic layer was washed with sat. NaHCO3 and concentrated under reduced pressure. The resulting residue was purified by ISCO silica gel column using 0 to 50% to EtOAc in hexane as eluting solvents and Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5u column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 305) as white lyophillate (36 mg, 52% yield). LCMS: RT=4.268 min [M+H] 672.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm. NMR: 400 MHz 1H (CDCl3) ppm 0.45-0.73 (m, 4 H), 3.51-3.59 (m, 1H), 3.76 (d, J=13.18 Hz, 1H), 4.22 (d, J=12.74 Hz, 1H), 6.13-6.44 (m, 1H), 6.66-6.76 (m, 3H), 6.97-7.08 (m, 3H), 7.10-7.23 (m, 5H), 7.42-7.50 (m, 1H), 7.95-8.03 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:43]=[C:38]([Cl:37])[C:39]([OH:54])=[C:40]([Cl:53])[CH:41]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][N:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 36.3 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyrimidin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (35 mg, 36% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.34 (s, 1H), 8.47 (s, 2H), 8.26 (m, 2H), 8.04 (d, J=8.8 Hz, 1H), 7.41 (s, 2H), 4.07 (m, 2H), 3.91 (m, 1H), 3.81 (m, 2H), 2.81 (s, 1H), 2.52 (m, 1H), 2.23 (tt, J=13.0, 5.7 Hz, 1H), 1.20 (s, 4H); ESI MS m/z 535 [C27H24Cl2N6O2+H]+; HPLC 100.0% (AUC), tR=10.30 min.
Reaction SMILES: N[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C([N:38](CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([C:34]4[C:26]([F:25])=[C:27]([CH:31]=[CH:32][C:33]=4[F:35])[C:28]([NH2:38])=[O:29])=[CH:3][CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: NC(=O)c1ccc(F)c(-c2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1F
Yield: 81.4 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is reacted with 0.194 g (1.1 mmol) of 2,4-difluorobenzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from ethyl acetate-hexane to give 0.37 g of crystals, m.p. 215°-217° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=O)[CH2:9][CH:10]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[C:11](=O)[N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH:10]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:11][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)CC(C(=O)N2CCCCC2)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCN(CCC(CN2CCCCC2)c2ccc(N)cc2)CC1

Procedure:
1-[(4-Nitrophenyl)acetyl]piperidine was alkylated with methyl -bromoacetate in the same manner as in Reference Example 47, hydrolyzed with 1 M sodium hydroxide aqueous solution in methanol, and then condensed with 1-methylpiperazine in the same manner as in Reference Example 5 to obtain 1-methyl-4-[3-(4-nitrophenyl)-4-oxo-4-piperidin-1-ylbutanoyl]piperazine (ESI: 389). This piperazine compound was subjected to the reduction of nitro group in the same manner as the catalytic hydrogenation shown in Reference Example 3 and then treated with lithium aluminum hydride to obtain 4-[3-(4-methylpiperazin-1-yl)-1-(piperidin-1-ylmethyl)propyl]aniline. ESI: 331.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])[C:3]=1[O:17][CH2:18][CH3:19].FC(F)(F)C(O)=[O:23].[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH2:33][C:27]([CH:32]2[CH2:31][CH2:30]2)=[O:23])=[C:4]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])[C:3]=1[O:17][CH2:18][CH3:19]
Reactant: CCOc1c(Br)ccc(C(=O)Cl)c1N(C)S(C)(=O)=O
Reactant: Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: CCOc1c(Br)ccc(C(=O)CC(=O)C2CC2)c1N(C)S(C)(=O)=O
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A suspension of 4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)benzoyl chloride (2.45 g) in toluene (35 ml) was added to a solution of tert-butyl 3-cyclopropyl-3-oxopropionate magnesium enolate (1.3 g) in toluene (15 ml) and stirred for 2 days. Trifluoroacetic acid (1.1 ml) was added and the mixture was warmed at 65° C. for 1.5 hours, then cooled, washed with water, the organic extract dried (anhydrous magnesium sulphate) and the solvent evaporated. Purification by chromatograhpy gave 1-[4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione (1.87 g) as a yellow semi-solid, NMR 1.05(m,2H), 1.2(m,2H), 1.5(t,3H), 1.75(m,1H), 3.0(s,3H), 3.3(s,3H), 4.2(brm,2H), 6.1(s,1H), 7.15(d,1H), 7.6(d,1H), 15.9(brs,1H).