Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH3:21][N:22]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cl-].[NH4+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1[C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([N:22]([CH3:21])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Reactant: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCCCC)c1
Temperature: 92.5 °C
Yield: 85.3 %

Procedure:
3 mg (0.013 mmol) of palladium acetate and then 9 mg (0.026 mmol) of 2-(dicyclohexylphosphino)biphenyl are added to a mixture of 505 mg (1.3 mmol) of ethyl (E)-3-(3-butoxy-4-iodophenyl)-2-methylacrylate prepared as described in Example 19h, 446 mg (1.7 mmol) of 3-(1-methyl-3-pentylureido)phenylboronic acid prepared as described in Example 24h and 1.3 mL of aqueous 2 M potassium phosphate solution in 6.5 mL of dimethylformamide. The reaction mixture is heated at 90-95° C. for 2 hours. The reaction medium is hydrolyzed in saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the brown oil obtained (1.5 g) is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 533 mg (85%) of ethyl (E)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methylacrylate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]([CH:22]=O)[N:11](CC3C=CC(OC)=CC=3)[N:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:35](I)=[CH:34][N:33]([Si](C(C)C)(C(C)C)C(C)C)[C:30]2=[N:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:35]([CH2:22][C:10]3[NH:11][N:12]=[C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=4)[CH:9]=3)=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C=O)cc1
Product: Fc1ccc(CNc2cc(Cc3c[nH]c4ncc(Cl)cc34)[nH]n2)cc1

Procedure:
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine P-2016 was prepared in three steps from 5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazole-3-carbaldehyde 113 and 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4 as shown in Scheme 19.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[N:5]([CH:22]3[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]3)[C:4]=2[N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([NH2:40])[CH:34]=[C:35]2[C:39]=1[NH:38][N:37]=[CH:36]2.FC(F)(F)C(O)=O>C(O)C(F)(F)F.C(OCC)(=O)C>[F:29][C:25]1([F:28])[CH2:24][CH2:23][CH:22]([N:5]2[C:4]3[N:3]=[C:2]([NH:40][C:33]4[CH:34]=[C:35]5[C:39](=[C:31]([F:30])[CH:32]=4)[NH:38][N:37]=[CH:36]5)[N:11]=[CH:10][C:9]=3[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@H:6]2[CH3:21])[CH2:27][CH2:26]1
Reactant: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Reactant: Nc1cc(F)c2[nH]ncc2c1
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Nc3cc(F)c4[nH]ncc4c3)nc2N1C1CCC(F)(F)CC1
Temperature: 125 °C
Yield: 40 %

Procedure:
To a solution of 3-[(7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile (208 mg, 0.5 mmol), 7-fluoro-1H-indazol-5-amine (113 mg, 0.75 mmol) in trifluoroethanol (2 mL) in a microwave reaction vial was added trifluoroacetic acid (171 mg). The vial was then sealed and heated in a microwave reactor at 125° C. for 30 minutes. The reaction mixture was then diluted with ethyl acetate (25 mL) and washed with aqueous saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4) and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (40%).
Reaction SMILES: O1CCCC1.[NH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(N(CC)CC)C>[OH:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][NH:6][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(CCCc1ccccc1)OCCCCCCCCCCCCBr
Reactant: NCC(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1)OCCCCCCCCCCCCNCC(O)c1ccccc1

Procedure:
According to method I (tetrahydrofuran, reflux 4 days) from 2-amino-1-phenylethanol and (12-bromo-1-dodecyl)4-phenylbutanoate. Working up by means of chromatography (ethyl acetate/petroleum ether 60-80/triethylamine 6:4:1). Recrystallized from diethyl ether. Melting point: 73°-74° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].O1[CH2:20][CH2:19]OCC1>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>[N:3]1[CH:20]=[CH:19][N:7]=[CH:6][C:2]=1[C:2]1[N:3]=[CH:4][S:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1scnc1Br
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Nc1scnc1-c1cnccn1
Temperature: 140 °C
Yield: 62 %

Procedure:
A mixture of tert-butyl 4-bromothiazol-5-ylcarbamate (420 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.15 mmol) and 2-tributyl-stannylpyrazine (930 mg, 2.5 mmol) in anhydrous dioxane (4 mL) was heated to 140° C. in a microwave reactor for 2 h. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes) to give the desired product (260 mg, 62%). 1H NMR (CDCl3) δ11.10 (s, 1H), 9.47 (d, J=1.4 Hz, 1H), 8.52 (t, J=2.0 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.40 (s, 1H), 1.58 (s, 9H); MH+ 279.0.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]([OH:12])=O)[N:5]=1)([O-:3])=[O:2].[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:40][CH3:41])=[N:31][N:32]3[CH:35]3[CH2:39][CH2:38][CH2:37]C3)=[CH:28][CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:40][CH3:41])=[N:31][N:32]3[CH:35]3[CH2:37][CH2:38][CH2:39]3)=[CH:28][CH:27]=2)[CH2:23][CH2:24][N:25]1[C:10](=[O:12])[CH2:9][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: O=C(O)Cc1n[nH]c([N+](=O)[O-])n1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4n[nH]c([N+](=O)[O-])n4)[C@@H](Cc4ccccc4)C3)ccc12

Procedure:
Prepared by the method outlined for Example 189 using (5-Nitro-1H-[1,2,4]triazol-3-yl)-acetic acid and ester 6-(S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (Example 56, Compound 144) as starting materials. Product as an oil. LC/MS (Method B) 2.56 min, [M+1]+ 529. Potency class ND.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]=1[CH3:13].Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[NH:26][N:25]=[C:24]([CH:27]3[CH2:29][CH2:28]3)[CH:23]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:27]1([C:24]2[NH:25][N:26]=[C:22]([NH:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:2]([CH3:1])[CH2:3][C:4]4[CH:12]=[CH:11][C:7]5[NH:8][CH:9]=[N:10][C:6]=5[C:5]=4[CH3:13])[N:20]=3)[CH:23]=2)[CH2:29][CH2:28]1
Reactant: CNCc1ccc2[nH]cnc2c1C
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(CN(C)c2nccc(Nc3cc(C4CC4)[nH]n3)n2)ccc2[nH]cnc12
Temperature: 120 °C

Procedure:
A tube was charged with 264 (40 mg, 0.23 mmol), 53 (100 mg, 0.57 mmol), and DIPEA (0.3 ml) in IPA (3 mL), degassed, sealed and heated at 120° C. overnight. After removal of the solvent in vacuo, the crude was purified by preparative HPLC to afford 25 mg (29%) of I-95 as white solid.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:21][C:19](=[O:20])[CH2:18][C@@H:17]([OH:22])[C@H:16]([CH3:23])[C@@H:15]([O:24][C@@H:25]2[O:30][C@H:29]([CH3:31])[CH2:28][C@H:27]([N:32]([CH3:34])[CH3:33])[C@H:26]2[OH:35])[C@@H:14]([CH2:36][CH:37]=[O:38])[CH2:13][C@@H:12]([CH3:39])[C:10](=[O:11])[CH:9]=[CH:8][C@:6]2([CH3:40])[O:7][C@H:5]2[C@@H:4]1[CH3:41].[C:42]([OH:51])(=[O:50])[CH:43]([CH:45]([C:47]([OH:49])=[O:48])[OH:46])[OH:44].O>C(OCC)C.C(O)C>[CH3:1][CH2:2][C@H:3]1[O:21][C:19](=[O:20])[CH2:18][C@@H:17]([OH:22])[C@H:16]([CH3:23])[C@@H:15]([O:24][C@@H:25]2[O:30][C@H:29]([CH3:31])[CH2:28][C@H:27]([N:32]([CH3:33])[CH3:34])[C@H:26]2[OH:35])[C@@H:14]([CH2:36][CH:37]=[O:38])[CH2:13][C@@H:12]([CH3:39])[C:10](=[O:11])[CH:9]=[CH:8][C@:6]2([CH3:40])[O:7][C@H:5]2[C@@H:4]1[CH3:41].[C:47]([CH:45]([CH:43]([C:42]([O-:51])=[O:50])[OH:44])[OH:46])([O-:49])=[O:48]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/[C@]2(C)O[C@H]2[C@@H]1C
Agent: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=C[C@]2(C)O[C@H]2[C@@H]1C
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 0.25 h

Procedure:
Dissolve 1 gm of rosaramicin in 50 ml of diethyl ether; add a solution of 250 mg of tartaric acid in 1.5 ml of ethanol. Stir the resulting mixture for about 15 minutes, then filter the precipitated salt. Wash the precipitate with diethyl ether; dry the precipitate and obtain thereby the title product, m.p. 129°-134° C., [α]D20 =-12° (C=0.3% water).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10]/[C:11](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:27]\[OH:28])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(CC(=O)c2ccncc2)c2ccccn2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)c1ccc(C(C/C(=N\O)c2ccncc2)c2ccccn2)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-pyridin-2-yl-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a yellow foam, MS (ESI+): m/z=347.2 ([M+H]+).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:35]=[CH:34][C:17]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[N:29]([CH:30]([CH3:32])[CH3:31])[C:28]([CH3:33])=[N:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.N>CO>[OH:4][CH2:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:35]=[CH:34][C:17]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[N:29]([CH:30]([CH3:32])[CH3:31])[C:28]([CH3:33])=[N:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(=O)OCC(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Agent: N
Solvent: CO
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(C(=O)CO)CC4)cc3)n2)n1C(C)C
Reaction time: 28 h

Procedure:
2-{4-[4-(2-Acetoxyacetyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 21; 330 mg) was stirred in MeOH (5 ml) at room temperature and 7N ammonia in MeOH (1.6 ml) was added. After 28 hours, the reaction was evaporated under reduced pressure. Chromatography on silica gel using MeOH:DCM (4:96 to 5:95), yielded the title compound as a yellow solid. (108 mg 36%). NMR: 1.39 (d, 6H), 2.46 (s, 3H), 3.05 (b s, 4H), 3.48 (b s, 2H), 3.61 (b s, 2H), 4.12 (d, 2H), 4.57 (t, 1H), 5.69 (septuplet, 1H), 6.92 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.47 (d, 2H), 8.31 (d, 1H), 9.15 (s, 1H); m/z 436.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[CH2:35][C:36]([OH:38])=[O:37])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23>Cl.O1CCOCC1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[CH2:35][C:36]([OH:38])=[O:37])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(CC(=O)O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.8 %

Procedure:
A suspension of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(carboxymethyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (1.499 g) in 2N hydrogen chloride in 1,4-dioxane (30 mL) was stirred overnight at room temperature and diluted with diethyl ether. The precipitates were collected and recrystallized from water to give 1.247 g of the title compound (79%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[F:26][C:27]([F:37])=[CH:28][C@H:29]1[C@H:31]([C:32](Cl)=[O:33])[C:30]1([CH3:36])[CH3:35].O>C(OCC)C>[F:26][C:27]([F:37])=[CH:28][C@H:29]1[C@H:31]([C:32]([O:9][CH2:8][C:7]2[C:2]([F:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]([F:12])=[C:5]([F:11])[C:6]=2[F:10])=[O:33])[C:30]1([CH3:35])[CH3:36]
Reactant: OCc1c(F)c(F)c(F)c(-c2ccccc2)c1F
Reactant: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)Cl
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](C=C(F)F)[C@@H]1C(=O)OCc1c(F)c(F)c(F)c(-c2ccccc2)c1F

Procedure:
To a stirred solution of 0.97 g (3.8 mmole) of 2,4,5,6-tetrafluoro[1,1'-biphenyl]-3-methanol and 1 ml of dry triethylamine in 8 ml of dry diethyl ether was added 4 ml of a dry diethyl ether solution of trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (0.95 mmole/ml). The resultant mixture was stirred at room temperature for approximately 18 hours, then poured into 50 ml of water. The organic phase was separated, washed with a 5% aqueous sodium bicarbonate solution followed by a water wash, then dried over anhydrous magnesium sulfate. The organic phase was filtered, and the filtrate evaporated under reduced pressure to give an oil. The oil was purified by column chromatography on silica gel, eluted with ethyl acetate:hexanes (10:90), to yield 0.92 g of (2,4,5,6-tetrafluoro[1,1'-biphenyl]-3-yl)methyl trans-3-(2,2-difluoroethenyl)-2,2-dimethylcyclopropanecarboxylate as a solid (m.p. 69°-72° C.).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:20]3[CH:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(I)cn1
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(Cl)nc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=311.3 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 2-chloro-5-iodopyridine.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])=[N:8]2)=[C:26]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Clc1ccc(CBr)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2OCc2ccccc2)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a mixture of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for as preparation see Intermediate 9) (76 mg, 0.340 mmol) and potassium carbonate (96 mg, 0.692 mmol) was added a solution of 1-(bromomethyl)-4-chloro-2-[(phenylmethyl)oxy]benzene (0.106 g, 0.340 mmol) in DMF (1 ml). The reaction was stirred overnight, at ambient temperature and under nitrogen. The suspension was filtered using a hydrophobic frit and the residue washed with methanol (1 ml). The filtrate was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The solvent was evaporated in vacuo to give the title compound as a white solid (27 mg); LCMS: (System 1) MH+=454, tRET=3.68 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[F:28]C1C=C(C=CC=1OCC1C=CC2C(=CC=CC=2)N=1)C(N(OC)C)=O>>[F:28][C:14]1[CH:15]=[C:10]([C:8](=[O:9])[CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][C:13]=1[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 3-Fluoro-N-methoxyl-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide provided the title compound. MS: (M+H m/z=373.1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[CH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccccc2B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Product: CCOC(=O)C1(c2ccccc2-c2ccc(-c3onc(C)c3C=CCCc3ccccc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-Bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and 1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:9])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>C1COCC1>[CH:4]1[CH:3]=[C:2]([CH2:6][C:7]([NH2:9])=[S:11])[S:1][CH:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)Cc1cccs1
Solvent: C1CCOC1
Product: NC(=S)Cc1cccs1
Yield: 54.5 %

Procedure:
To a solution in THF (200 mL) of 2-thiopheneacetamide (4.04 g, 28.6 mmol), prepared as in step 1, was added P4S10 (12,7 g, 28.6 mmol), and the vigorously stirred reaction mixture was placed in a Bransonic 221 bath and irradiated with ultrasound for 30 min. The reaction mixture was filtered and the tiltrate was concentrated in vacuo. The crude product was taken up in CH2Cl2 and decanted from the solid residue. Pure 2-thiophenethioacetamide (2.45 g, 54% yield) was obtained by chromatography on silica gel (CH2Cl2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH:7]([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:8]1([C:7]([C:6]2[CH:15]=[CH:16][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=2)=[O:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
A solution of 4-(trifluoromethyl)benzhydrol (1.836 g, 7.3 mmol) in anhydrous DCM (65 mL) was treated with manganese(IV) oxide (<5 micron, activated) (5.7 g, 66 mmol). The resulting suspension was stirred at rt for 12 days. The catalyst was removed by filtration through a Celite® brand filter agent pad. The filtrate was concentrated, and the resulting solid was dried under high vacuum to afford the title compound as a white solid.