Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:25]=[C:26]([NH:30][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=4[F:11])[CH:27]=[CH:28][CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)c3c(F)cccc3F)c1)cn2C1CCCC1
Temperature: 120 °C
Yield: 48.4 %

Procedure:
2,6-difluorobenzoyl chloride (82.1 mg, 0.47 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (100 mg, 0.31 mol) in pyridine (3 mL). The resulting solution was heated to 120° C. for 1 h at this time the reaction was quenched with water and concentrated. The residue was dissolved in EtOAc and washed with 1N NaOH and water. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 97:3) afforded the title compound as a white solid (105 mg, 73%). MS: 462.2 (MH+); HPLC Rf: 5.70 min. (HPLC method 4).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH3:36])=[O:5])[CH3:2].C1(C)C=CC=CC=1.[C:44](Cl)([Cl:46])=[O:45]>>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[C:44]([Cl:46])=[O:45])[CH2:8][C@@H:7]1[CH3:36])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)Cl)C[C@@H]1C
Yield: 76 %

Procedure:
cis-4-((3,5-Bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (prepared in a manner analogous to the procedures described for Examples 3A-3E) (146 mg, 0.28 mmol) was dissolved in 2 mL of a 1.93M phosgene solution in toluene (3.9 mmol). After heating at reflux for 1.5 h, the sample was concentrated in vacuo to afford the title product (125 mg, 76%). 1H NMR (CDCl3) δ 1.2-1.6 (m, 7H), 2.2-2.4 (m, 1H), 4.2-4.6 (m, 4H), 5.2-5.6 (m, 2H), 7.1 (s, 1H), 7.5-7.9 (m, 5H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[CH3:37])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCNCC(O)COc1ccc(CCOCC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1.CCCCCC>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]=[O:21])([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(C)Oc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Oc1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A solution of 1-bromo-3-iso-propyloxybenzene (2.16 g, 10 mmol) in dry THF (30 mL) was cooled to −78° C. and n-BuLi (4.8 mL of a 2.5 m solution in hexane, 12 mmol) was added. The resulting solution was stirred 0.5 hours and DMF (7.3 g, 10 mmol) was added at −78° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. Purification on silica gel with 25% ethyl acetate/hexane afforded the title compound (1.64 g, 100%).
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][N:22]=[N:21][C:20]=1[NH2:25]>O>[CH3:6][O:5][C:3]([C:2]1[N:21]2[N:22]=[CH:23][CH:24]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[C:20]2=[N:25][C:7]=1[CH2:8][CH3:9])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Cc1ccc(-c2ccnnc2N)c(C)c1
Solvent: O
Product: CCc1nc2c(-c3ccc(C)cc3C)ccnn2c1C(=O)OC
Temperature: 155 °C
Yield: 37 %

Procedure:
Methyl 2-chloro-3-oxopentanoate (5 mL) was added to 4-(2,4-dimethylphenyl)-3-pyridazineamine (640 mg, 3.2 mmol), and the mixture was heated at 155° C. for 30 minutes. Water was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:N-hexane=1:3) to give the title compound (373 mg, 37%) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH2:25])=[N:21]1>>[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:21]1
Reactant: Nc1ncn(Cc2ccc(Cl)cc2Cl)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4ccc(Cl)cc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2,4-dichloro-benzyl)-1H-[1,2,4]triazol-3-ylamine (ART-CHEM). The title compound was obtained as a colorless solid (Yield=67%). MS ISP (m/e): 424.1 (100) & 426.0 (81) [(M+H)+].
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][C:11]([NH2:14])=[CH:12][N:13]=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.B>C1COCC1>[N:1]1([CH2:7][C:9]2[S:10][C:11]([NH2:14])=[CH:12][N:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cnc(C(=O)N2CCOCC2)s1
Agent: B
Solvent: C1CCOC1
Product: Nc1cnc(CN2CCOCC2)s1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
To a solution of 2-(4-morpholinylcarbonyl)-1,3-thiazol-5-amine (Preparation 26, 1.0 g) in THF (10 mL) under nitrogen at ambient temperature is added borane (1.0 M solution in THF, 9.39 mL). The bright yellow mixture is heated to reflux (85° C.) for 1 h. The mixture is cooled to ambient temperature, quenched with aq. NH4Cl, and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed. The residue is purified by column chromatography (eluent 2% MeOH/CH2Cl2) to afford 329 mg (35%) of the title compound as a yellow oil. Physical characteristics: 1H NMR (CDCl3) δ 2.49, 3.61, 3.65, 6.84; MS (ESI+) m/z 200 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:21][CH3:20])=[O:23])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CNC(=O)c1cccc(-c2cccn3nc(Nc4ccccc4OC)nc23)c1

Procedure:
3-[2-(2-Methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-N-methyl-benzamide was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 3-methylaminocarbonylbenzeneboronic acid (31.0 mg, 0.173 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2c and was isolated as a yellow solid (0.048 g, 82%). MP=199-202° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48-8.44 (m, 2H), 8.40 (dd, J=7.9, 1.3 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.65-7.57 (m, 3H), 7.07-6.99 (m, 4H), 6.30 (br s, 1H), 3.92 (s, 3H), 3.07 (d, J=4.9 Hz, 3H). MS=374 (MH)+.
Reaction SMILES: CCN(CC)CC.[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[S:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]=1)=[O:20].[Cl:30][CH2:31][C:32](Cl)=[O:33].C([O-])(O)=O.[Na+]>ClCCl>[Cl:29][C:27]1[S:26][C:24]2[NH:25][C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][C:32](=[O:33])[CH2:31][Cl:30])=[O:20])=[CH:22][C:23]=2[CH:28]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Et3N (3 mL, 21.6 mmol) was added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 3.11 g, 6.98 mmol) in anhydrous dichloromethane (55 mL) and stirred at ambient temperature for 5 miuntes. The suspension was cooled to −78° C. and chloroacetylchloride (611 μL, 7.68 mmol) was added and the reaction was warmed to 0° C. and stirred at this temperature for 3 hours. NaHCO3 (50 mL) was added, the phases were separated and the aqueous phase was extracted with THF (2×50 mL). The combined organic fractions were washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was triturated (THF:isohexane, 1:5), collected by filtration, washed with hexane (20 mL) and dried to give the title compound (1.92 mg, 68%) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([O-:3])=[O:2].Cl.[CH3:13][NH:14][O:15][CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:9]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1)=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 3-nitro-1H-pyrazole-5-carboxylic acid (15.7 g, 1.0 eq., 100 mmol), N,O-dimethylhydroxylamine hydrochloride (19.5 g, 2.0 eq., 200 mmol), HATU (76.0 g, 2.0 eq., 200 mmol), triethylamine (40.4 g, 4.0 eq., 400 mmol), and dichloromethane (300 mL). The reaction mixture was stirred at room temperature for overnight. The solvent was removed under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 287a (16.0 g, 80%) as white solid. MS-ESI: [M+H]+ 201.1
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][CH:19]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[CH:32]1[CH2:34][O:33]1>CCO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH2:15][N:16]([CH2:34][CH:32]([C:25]4[C:24]5[C:29](=[CH:30][CH:31]=[C:22]([O:21][CH3:20])[CH:23]=5)[N:28]=[CH:27][CH:26]=4)[OH:33])[CH2:17][CH2:18][CH:19]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2nccc(C3CO3)c2c1
Reactant: C1=C(CNCc2ccc3c(c2)OCCO3)CNCC1
Solvent: CCO
Product: COc1ccc2nccc(C(O)CN3CCC=C(CNCc4ccc5c(c4)OCCO5)C3)c2c1

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-amine (0.06 g, 0.23 mmol) and 6-methoxy-4-oxiranylquinoline (0.06 g, 0.29 mmol) in EtOH (2 ml) was heated at 80° C. for 14 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (DCM/MeOH 9/1).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOC(C)=O.[NH4+].[Cl-]>C1COCC1>[O:8]1[CH:9]=[CH:10][C:6]([C:4](=[O:5])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7]1
Reactant: CON(C)C(=O)c1ccoc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)c1ccoc1
Reaction time: 5 h
Yield: 63.2 %

Procedure:
A solution of N-methoxy-N-methylfuran-3-carboxamide (913 mg, 5.89 mmol) in anhydrous THF (10 mL) was cooled to −78° C. under nitrogen, and a solution of benzylmagnesium chloride in THF (2 mol/L, 3.53 mL) was added through a syringe. The reaction mixture was stirred at this temperature for 5 hours. TLC (PE:EtOAc=5:1) indicated reaction was nearly complete, saturated NH4Cl solution (20 mL) was added to quench the reaction, and the aqueous layer was extracted with EtOAc (80 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford 1-(furan-3-yl)-2-phenylethanone as a yellow oil (696 mg, yield: 63.2%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(COC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
Tert-butyl 4-(4-trifluoromethylbenzyloxy)-piperidine-1-carboxylate (2.56 g, 7.12 mmol) prepared in Reference Example 122 was dissolved in methylene chloride (20 ml), to which trifluoroacetic acid (10 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. This solution was neutralized with sodium hydroxide aqueous solution and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylbenzyloxy)piperidine (1.85 g, yield 99%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13]Br>C(O)(=O)C.O>[Br:13][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:12]
Reactant: BrBr
Reactant: O=C1CCCc2cc(O)ccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2c1ccc(O)c2Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
To a solution of 4.3 g of 6-hydroxy-1-teralone in 0 ml of acetic acid and 6 ml of water with stirring under ice cooling is added dropwise a solution of 5.1 g of bromine in acetic acid for 8 minutes. After addition, the mixture is stirred unde ice cooling for 5 minutes and at room temperature for 30 minutes. To the reaction mixture is added 170 ml of ice-cold water. The insoluble substance is collected by filtration, dried and recrystallized from a mixture of hexane, ethyl acetate and ethanol to give 4.8 g of 5-bromo-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone, melting at 183°-186° C.
Reaction SMILES: Cl.[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:22]N(C)C.C(Br)C.[CH2:29]([OH:31])[CH3:30]>>[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:22][O:31][CH2:29][CH3:30]
Reactant: CCO
Reactant: COc1ccc(Cc2oc3ccc(CN(C)C)c(O)c3c2C)cc1
Agent: Cl
Solvent: CCBr
Product: CCOCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O

Procedure:
A mixture of (177) (Example 45) (0.1 g, 0.28 mmol), ethyl bromide, (1 mL) and ethanol (5 mL) was refluxed for 6 h. The solvent was evaporated, the residue was chromatographed on preparative tlc to give the title compound.
Reaction SMILES: [C:1]([CH:6]([C:18]([OH:20])=O)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:27][C:28]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:29]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>C(Cl)Cl.CN(C)C=O>[C:30]([C:29]1[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=1[NH:27][C:18](=[O:20])[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cl)ccc1C(=O)c1ccccc1

Procedure:
A suspension of 45.0 g. of 2-carbethoxy-N-(benzyloxycarbonyl)glycine in 120 ml. of dry methylene chloride, cooled to -20° C., is treated portionwise with 30 g. of phosphorus pentachloride and stirred for 30 minutes at -20° C. to -10° C. To the now clear solution, there is added at the same temperature a solution of 27.7 g. of 2-amino-4-chlorobenzophenone and 1 ml. of dimethylformamide in 120 ml. of dry methylene chloride. The mixture is concentrated under reduced pressure at 40°-45° C. The residue is partitioned between methylene chloride and 10% aqueous soda solution and the methylene chloride phase is dried over sodium sulfate and evaporated to dryness. There is obtained a reddish-colored resin of crude 2'-benzoyl-2-[(benzyloxycarbonyl)amino]-2-carbethoxy-5'-chloroacetanilide, which is then immediately reacted with 130 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After stirring at room temperature for 90 minutes, the obtained solution is concentrated at 45° C. and the oily residue partitioned between water and ether. The aqueous solution is made weakly alkaline with solid sodium bicarbonate while cooling with ice. The separated base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated to dryness. The resulting oil is dissolved in a mixture of 180 ml. of toluene and 180 ml. of glacial acetic acid and heated at 80° C. for 90 minutes. The solution is concentrated to an oil and is crystallized from ether so that there is obtained 8-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester, having a melting point of 214°-217° C. (decomposition). Recrystallization from acetonitrile does not increase the melting point.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]1=2.[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:39])[CH:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:2][CH2:3][O:4][CH:5]2[C:12]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=3[O:10][CH2:9][O:8][C:7]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:6]2=3)=[CH:33][CH:34]=1)[CH3:24]
Reactant: Clc1ccc2c(c1)C(OCCBr)c1cc(Cl)ccc1OCO2
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3cc(Cl)ccc3OCOc3ccc(Cl)cc32)cc1)OCC
Temperature: 60 °C
Yield: 52.9 %

Procedure:
To a solution of 12-(2-bromo-ethoxy)-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene (404 mg, 1.0 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in dry toluene (6 mL) was added potassium carbonate (276 mg, 2.0 mmol) and 18-crown-6 (528 mg, 2.0 mmol). The mixture was heated at 60° C. for 16 h. The mixture was filtered, and concentrated in vacuo. The residue was submitted to flash chromatography using toluene/ethyl acetate (19:1) as eluent to give 297 mg (53%) of the title compound; 1H NMR (300 MHz, CDCl3) δ1.18 (t, 3H), 1.25 (t, 3H), 2.96 (d, 2H), 3.30-3.42 (m, 1H), 3.55-3.65 (m, 1H), 3.90-3.95 (m, 2H), 4.0 (t, 1H), 4.15-4.25 (m, 4H), 4.55 (d, 1H), 5.87)d, 1H), 6.18 (s, 1H), 6.88-6.95 (m, 4H), 7.10-7.25 (m, 4H), 7.60 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[O:18][CH3:19].C[Si](C)(C)[O:22][CH:23]=[C:24]([CH3:26])[CH3:25]>[F-].[F-].[Zn+2].CN(C=O)C>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[C:24]([CH3:26])([CH3:25])[CH:23]=[O:22])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)=CO[Si](C)(C)C
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1Br
Agent: [F-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1C(C)(C)C=O
Temperature: 80 °C

Procedure:
To a flask purged with nitrogen was added Pd(tBu3P)2 (26 mg, 0.050 mmol), ZnF2 (52 mg, 0.50 mmol) and DMF (4 mL). The reaction mixture was allowed to stir for 10 minutes before benzyl 4-bromo-3-methoxy-benzoate (323 mg, 1.01 mmol) was added followed by trimethyl(2-methylprop-1-enoxy)silane (277 μL, 1.51 mmol). The reaction was heated at 80° C. overnight. The crude mixture was quenched with brine and extracted with EtOAc 3 times. The organic layer was dried over sodium sulfate and the solvent was evaporated to give benzyl 3-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzoate. ESI-MS m/z calc. 312.4, found 313.4 (M+1)+; Retention time: 3.27 minutes (4 min run).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: N#Cc1cn[nH]c1N
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(C)(=O)=O
Yield: 52.1 %

Procedure:
A mixture of 0.196 g (1.82 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.54 g (1.82 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 324 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-ethyl-methanesulfonamide as a yellow solid (yield 52.4%).