Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[C:18]([C:19]([O:21][CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24](=[O:25])[O:23]2)=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:13]1[C:18]([C:19]([O:21][CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24](=[O:25])[O:23]2)=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C1OC(OC(=O)c2cccnc2Cl)c2ccccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1C
Product: O=C1OC(OC(=O)c2cccnc2Nc2cccc(C(F)(F)F)c2)c2ccccc21
Yield: 82.2 %

Procedure:
To 80 ml of xylene, under reflux, m-trifluoromethylaniline (32.2 g) is added. Then, 29 g of phthalidyl 2-chloro-3-pyridinecarboxylate prepared in accordance with Example 1, Supra (divided in two fractions) is poured into the mixture with an interval of 15 minutes between each addition. The reaction mixture so obtained is maintained under reflux for 5 hours, and then cooled by pouring the mixture into an ice/water bath. To allow the complete crystallization of the desired product, the poured reaction mixture is maintained for 2 hours at a temperature of 0°-5° C. The precipitate is collected by filtration and dried under vacuum, at a temperature of 40° C. A yield of 34.1 g (82.3% of theory) of phthalidyl 2-(3-trifluoromethylanilino)-3-pyridinecarboxylate is obtained (m.p. 159°-162° C.). Recrystallizing the compound with 6 volumes of ethyl acetate, 28.4 g (68.5% yield) is obtained (m.p. 164°-5° C.).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[NH:39][C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[N:32]=2)[CH2:27][CH2:26]1>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:26][CH2:27][CH:28]([C:31]5[NH:39][C:34]6=[N:35][CH:36]=[CH:37][CH:38]=[C:33]6[N:32]=5)[CH2:29][CH2:30]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2[nH]c(C3CCNCC3)nc2c1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Agent: Cl
Product: c1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CCC(c4nc5cccnc5[nH]4)CC3)cc2)cc1
Yield: 68.4 %

Procedure:
By reacting 150 mg (0.5 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde with 122 mg (0.6 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-b]pyridine hydrochloride salt as described in example 6.0 the desired compound (166 mg) was obtained after purification on silicagel.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])#[N:4]>C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:2][CH3:1])=[O:9])#[N:4]
Reactant: CN
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C#N)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 40% aqueous methylamine solution (20 ml) and THF (30 ml) was cooled to 5° C., and 3-cyanobenzoyl chloride (1.89 g) was slowly added. The mixture was stirred for one hr. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated. The residue was recrystallized from ethyl acetate to give the title compound (1.14 g) as colorless needle crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[O:15]=[C:16]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][N:17]1[CH2:33][C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:35]=[C:34]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:33][N:17]1[CH2:18][CH2:19][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]1=[O:15]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1
Reaction time: 60 h

Procedure:
A solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (0.037 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring for approximately 60 hours, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.40 (m, 13H), 4.55-4.80 (m, 2H), 4.25 (s, 2H), 3.60-3.85 (m, 2H), 3.45-3.55 (m, 2H), 2.70-2.90 (m, 4H); MS (ESI+) m/z 471 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:21]1[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:19]([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[CH:18]=2)[CH:20]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
In a similar manner as described for example B11, 102.8 mg of 4-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH2:19]([O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH:27][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[CH3:18]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: CCOc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 63.6 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol), m-phenetidine (19 μl, 0.144 mmol), and 2N HCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried to give a yellow solid (22 mg, 63%). 1H NMR (CDCl3): 8.88-8.85 (m, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.93-7.88 (m, 1H), 7.61 (s, 1H), 7.48-7.44 (m, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.05 (s, 1H), 6.89-6.81 (m, 3H), 4.07 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: CC(C)=CCBr
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CC=C(C)C)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (25 mg, 71%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 4-bromo-2-methyl-2-butene (23 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.65 (s, 3H), 1.79 (s, 3H), 2.12-2.22 (m, 3H), 2.24-2.40 (m, 1H), 2.57 (se, J=7.7 Hz, 2H), 2.72 (t, J=6.6 Hz, 2H), 2.74-2.84 (br, 1H), 3.05-3.45 (m, 6H), 3.59-3.77 (m, 1H), 3.86 (s, 3H), 5.42-5.55 (br, 1H), 6.83 (s, 1H), 6.85 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.17-7.25 (m, 2H) ppm. MS (CI, NH3): 457.2 (base, M+H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH3:26])[CH2:4][C:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:6]=1[NH:21][C:22](=O)[CH3:23])[CH3:2].[Cl-].[NH4+].C([NH2:32])(=O)C>>[CH2:1]([CH:3]([C:4]1[C:5]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:21]=[C:22]([CH3:23])[N:32]=1)[CH2:25][CH3:26])[CH3:2]
Reactant: CC(N)=O
Reactant: CCC(CC)Cc1c(C)c(C)n(-c2c(C)cc(C)cc2C)c1NC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(CC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Yield: 59.3 %

Procedure:
A mixture of N-[3-(2-ethyl-butyl )4,5-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrrol-2-yl]-acetamide (100 mg, 0.27 mmol), ammonium chloride (290 mg, 5.42 mmol), and acetamide (1.635 g) was heated to reflux for 2 hours. The mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 56 mg of the title compound as a dark oil. The oil was purified through silica gel column chromatography to give the title compound as a yellow oil. 1H-NMR (CDCl3) δ 0.85(t, 6H), 1.70-2.0(m, 4H), 1.83(s, 6H), 1.99(s, 3H), 2.36(s, 3H), 2.44(s, 3H), 2.61 (s, 3H), 3.26(m, 1H), 7.00(s, 2H) ppm.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[F-].[Cs+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH:36]=[C:37]([C:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:22])[C:12]=3[C:10](=[O:11])[NH:9][CH2:8][CH:5]3[CH2:6][CH2:7][C:2]([F:24])([F:1])[CH2:3][CH2:4]3)[N:17]=2)[CH2:38][CH2:39]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, cesium fluoride, 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and bis(triphenylphosphine)palladium(II) dichloride. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (t, J=5.82 Hz, 1H), 8.03-8.05 (m, 1H), 7.94-8.00 (m, 2H), 7.78 (d, J=9.01 Hz, 1H), 6.89 (s, 1H), 4.12 (s, 2H), 3.57 (t, J=5.5 Hz, 2H), 3.28 (t, J=6.23 Hz, 2H), 2.73 (s, 2H), 2.02-2.04 (m, 2H), 1.74-1.87 (m, 5H), 1.43 (s, 9H), 1.30-1.32 (m, 2H). m/z: 519.0 [M+H]+
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([CH:5]1[CH2:6][CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Product: O=C(NCC1CC(C(=O)Nc2ccc(N3CCOCC3=O)cc2F)CC1O)c1ccc(Cl)s1

Procedure:
In analogy to example 21C, (1SR,3RS,4SR)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1RS,2SR,4SR)-4-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentylmethyl}-amide. Orange solid. MS: 496.3. ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:16]1([CH2:22][SH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH2:22]([S:23][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)/C=C/c1cc(Br)cnc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)cnc1Cl
Temperature: 80 °C
Yield: 104.1 %

Procedure:
A vial was charged with (E)-ethyl 3-(5-bromo-2-chloropyridin-3-yl)acrylate (660 mg, 2.272 mmol), phenylmethanethiol (296 mg, 2.385 mmol), Xantphos (131 mg, 0.227 mmol), Pd2(dba)3 (104 mg, 0.114 mmol), 1,4-dioxane (9086 μl), and Hunig's base (793 μl, 4.54 mmol). The vial was purged with argon and the mixture was heated at 80° C. for 1 h. Water and EtOAc were added, and the layers were separated. The organic portion was dried, filtered and concentrated. The crude material was purified by silica gel chromatography, 0-50% EtOAc/heptane to provide (E)-ethyl 3-(5-(benzylthio)-2-chloropyridin-3-yl)acrylate (790 mg, 2.366 mmol, 104% yield) as a yellow oil. m/z (ESI) 334.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu](I)I>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: Cc1ncc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Yield: 15.4 %

Procedure:
A solution of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (100 mg), 2-methyl-1H-imidazole (42 mg), copper iodide (14 mg) and cesium carbonate (236 mg) in DMF (2 mL) was stirred at 100° C. overnight. The reaction mixture was filtered, water (10 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 50→100% ethyl acetate/hexane) to give the title compound (18 mg, 15%) as a pale-yellow oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][O:6][NH2:7].[CH:9]([C:11]1[CH:16]=[CH:15][N:14]2[C:17]([C:20]3[CH:21]=[C:22]([C:26]4[CH:30]=[CH:29][S:28][C:27]=4[C:31]#[N:32])[CH:23]=[CH:24][CH:25]=3)=[CH:18][N:19]=[C:13]2[CH:12]=1)=O>>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][O:6][N:7]=[CH:9][C:11]1[CH:16]=[CH:15][N:14]2[C:17]([C:20]3[CH:21]=[C:22]([C:26]4[CH:30]=[CH:29][S:28][C:27]=4[C:31]#[N:32])[CH:23]=[CH:24][CH:25]=3)=[CH:18][N:19]=[C:13]2[CH:12]=1
Reactant: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Reactant: CN(C)CCON
Agent: Cl
Product: CN(C)CCON=Cc1ccn2c(-c3cccc(-c4ccsc4C#N)c3)cnc2c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 14 using O-(2-dimethylaminoethyl)hydroxylamine hydrochloride (144 mg, 0.82 mmol) and 3-[3-(7-formylimidazo[1,2-α]pyridin-3-yl)phenyl]thiophene-2-carbonitrile (90 mg, 0.27 mmol) to afford a yellow solid (42 mg, 38%), essentially as a single geometric isomer, m.p. 74-75° C. 1H NMR (360 MHz, CDCl3) δH 2.33 (6H, s), 2.67-2.71 (2H, m), 4.30-4.34 (2H, m), 7.33-7.37 (2H, m), 7.63-7.70 (4H, m), 7.79 (1H, s), 7.91 (1H, s), 8.15 (1H, s), 8.45 (1H, d, J 7); m/z (ES+) 416 (M++H).
Reaction SMILES: [CH2:1]=[CH2:2].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH:1]([C:3]1[CH:8]=[C:7]([C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH2:2])[CH:6]=[CH:5][CH:4]=1)=[CH2:2]
Reactant: c1ccccc1
Reactant: C=C
Product: C=Cc1cccc(C(=C)c2ccccc2)c1

Procedure:
When benzene is alkylated with ethylene in the presence of an alkylation catalyst, a reaction product containing unreacted benzene, alkylbenzenes, polyalkylbenzenes and heavier products is obtained. The above 1-(3-ethylphenyl)-1-phenylethane of the formula (V) is recovered as a fraction mainly containing components having a boiling point of 285° to 290° C. (atmospheric pressure basis) by distillation such as reduced-pressure distillation. The fraction is then dehydrogenated in the presence of a dehydrogenation catalyst, and if necessary, it is followed by distillation, to obtain 1-(3-vinylphenyl)-1-phenylethylene of the formula (III).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=2[F:34])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3c(F)cccc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.26 mmol) was added to a stirred solution of {6-chloro-4-[4-(2,6-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 0.064 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(2,6-difluoro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.029 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s, 1 H) 8.18 (d, J=7.83 Hz, 2 H) 7.98 (d, J=8.30 Hz, 1 H) 7.92 (s, 1 H) 7.81-7.89 (m, 1 H) 7.59 (d, J=7.82 Hz, 2 H) 7.49 (dd, J=8.80, 1.90 Hz, 1 H) 7.35-7.44 (m, 2 H) 6.97 (s, 1 H) 3.85 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C25H16ClF2O4S [(M−H)−] 485, obsd. 485.2.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[NH:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.O.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>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][C:2]([C:35]2[CH:36]=[N:32][NH:33][CH:34]=2)=[CH:7][N:6]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CN(c1cnc(-c2cn[nH]c2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
Under N2, a mixture of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (64 mg, 0.127 mmol), 4-pyrazoleboronic acid pinacol ester (37 mg, 0.19 mmol), Pd(PPh3)4 (29 mg, 0.0254 mmol), Cs2CO3 (124 mg, 0.381 mmol) in 1,4-Dioxane (3 mL)/water (0.3 mL) was stirred at reflux for 14 h. It was then cooled to ambient temperature, diluted with EtOAc and H2O, and extracted with EtOAc. The combined extracts was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[N:5]([CH:12]=[CH:13][N:14]=3)C=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.N>Cl>[Br:1][C:2]1[C:3]([C:4]2[NH:14][CH:13]=[CH:12][N:5]=2)=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:7]
Reactant: Brc1cccc2ncn3ccnc3c12
Agent: Cl
Agent: N
Product: Nc1cccc(Br)c1-c1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
5. 11.6 g of 10-bromoimidazo[1,2-c]quinazoline are stirred in 170 ml of 6N hydrochloric acid at 90° C. for 6.5 h. and then cooled in an ice bath. The reaction solution is poured into 30 ml of 25% aqueous ammonia and 50 g of ice and stirred for 10 min. The crystals are filtered off, washed with water and dried in a vacuum. 9.85 g of 3-bromo-2-(1H-2-imidazolyl)-aniline are obtained. The aqueous phase is saturated with sodium chloride and extracted three times with chloroform. After evaporation of the organic extracts in a vacuum, there are obtained a further 1.52g of 3-bromo-2-(1H-2-imidazolyl)-aniline. The substance can be recrystallized from water. M.p. 164°-165° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]([CH3:24])[CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]([CH3:23])[CH3:24])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(C(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7yl)oxy]acetate (4.2 gm., 0.011 mole) is added to a solution composed of 20% aqueous sodium hydroxide solution (4.32 ml., 0.022 mole) and methanol (45 ml.). The mixture is stirred and heated at reflux for two hours and then concentrated in vacuo at 50° C. The residue is dissolved in water (50 ml.) and made acid to Congo red paper with 6 normal hydrochloric acid. The solid that separates is removed by filtration, washed with water, then with a little methanol and finally with a little ether. After drying, the product is recrystallized from acetic acid to give pure [(5,6-dichloro-9a-isopropyl-3-oxo-1,2,9,9a-tetrahydro-3H fluoren-7-yl)oxy]acetic acid. Using a procedure similar to that described in Example 25, except that in Step A there is substituted for the [(6,7-dichloro-2-isopropyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid, an equimolar amount of: