Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([OH:30])=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([OH:30])=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: O=C(O)CBr
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)CP(=O)(O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.002525 mole) in chloroform (10 ml) was added triethylamine (1.16 ml, 0.00833 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (1.06 ml, 0.00833 mole) was added to the above solution dropwise, followed by bromoacetic acid (0.36 g, 0.00277 mole). The ice bath was removed and the mixture stirred at room temperature for 3 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (0.6 g) was dissolved in 30 ml ether; hexane was added dropwise to get a turbid solution and left at room temperature overnight to complete the crystallization. The resulting product was cooled in the freezer for 12 hours, filtered and the solid was washed very thoroughly with hexane (50 ml), ether (50 ml) and again very thoroughly with hexane (50 ml), ether (50 ml) in that order. The solid was vacuum dried to get 0.5 g (83%) of title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:18]C)[CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]1[OH:17])C.N.CCO>CCOCC>[CH3:18][N:3]([CH3:1])[CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:16][C:15]2[CH2:14][CH:13]=[CH:12][CH2:11][C:10]=2[CH2:9][C@H:8]1[OH:17]
Reactant: CCN(CC)CCC[C@@H]1Cc2ccccc2C[C@H]1O
Agent: N
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCC[C@@H]1CC2=C(CC=CC2)C[C@H]1O
Reaction time: 0.5 h

Procedure:
A solution of 14.6 g (66.6 mmol) of trans-3-[3-(diethylamino)propyl]-1,2,3,4-tetrahydro-2-naphthalenol in 125 ml of ether is added to 1 liter of NH3 (liquid). To this stirred solution is added 10 g of Li in pieces over 10 minutes. When the addition is complete, the reaction mixture is stirred for 30 minutes, after which time absolute EtOH (~ 150 ml) is added dropwise until the blue color is discharged. The NH3 is then allowed to evaporate, the residue is diluted with water, and this thoroughly extracted with ether. The combined ether extracts are washed with saturated aqueous NaCl, dried, and concentrated in vacuo to 13.4 g (92%) of the title compound as an oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:2][C:1](=[O:3])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 88 %

Procedure:
To a suspension of 4-(carboxymethyl)benzoic acid (2.43 g, 13.5 mmol) in methanol (30 mL) was added thionyl chloride (50 μL, 0.67 mmol). The reaction mixture was stirred at room temperature for 5.5 h, and a clear solution was obtained. The solvent was removed under reduced pressure. The residue was taken up in ether (100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and water (30 mL). The combined NaHCO3 and water extract was acidified with concentrated HCl in an ice bath. The white precipitation was collected and washed with water, dried to yield 2.30 g (88%) compound 150 as white solid. The material was used without further purification. mp 134-136° C. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 5H), 7.40 (d, J=8.2 Hz, 2H), 8.07 (d, J=8.2 Hz, 2H). LCMS (ESI), m/z, 193 (M−H)−.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]=[N:28][N:29]([CH3:31])[N:30]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]=[N:28][N:29]([CH3:31])[N:30]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn(C)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nnn(C)n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.6 %

Procedure:
In THF (4.3 ml)/methanol (3.2 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.43 g). To the solution was added 1N sodium hydroxide solution (4.3 ml), and the mixture was stirred at room temperature for 14 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=5/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.37 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[C:12]([CH:23]([CH3:25])[CH3:24])[N:13]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:9][CH:8]=1)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.[Li]N([Si](C)(C)C)[Si](C)(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[CH2:28][NH:27][C:26]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:8][CH:9]=2)[N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:12]=1[CH:23]([CH3:24])[CH3:25])=[O:37]
Reactant: C1COCCN1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2n1Cc1ccccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N3CCOCC3)cc2n1Cc1ccccn1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indol-6-yl trifluoromethanesulfonate (Compound 202, 100 mg, 0.18 mmol) in toluene (10 ml) at 25° C., bubbled with argon then added morpholine (22 mg, 0.25 mmol), LiN(TMS)2 (1M in THF, 0.37 ml, 0.40 mmol), Pd2 (dba)3 (3.2 mg, 0.0035 mmol), and X-Phos (4 mg, 0.011 mmol). The reaction was stirred for 12 h at 110° C., diluted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([N:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH3:16])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([N:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH3:16])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:8]
Reactant: Cc1cc(F)ccc1N(C)C1CN(c2ncc(Cl)cc2C(=O)O)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(N(C)c4ccc(F)cc4C)C3)CC2)cc1
Yield: 70.6 %

Procedure:
The title compound (D171) (58 mg) was prepared according to the experimental procedure described in Description 169 (reaction time 2 h) starting from 5-chloro-2-(3-((4-fluoro-2-methylphenyl)(methyl)amino)azetidin-1-yl)nicotinic acid (D120) (55 mg, 0.157 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (35.8 mg, 0.157 mmol).
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>O.C(O)COCCO>[NH2:18][C:17]1[C:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Nc1cc(C(=O)O)cc(OCc2ccccc2)c1Cc1ccccc1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 4-benzoyl-3-benzyloxy-5-nitrobenzoic acid (2.7 g), 98% aqueous hydrazine hydrate (4.5 ml), potassium hydroxide (1.5 g) in water (3.0 ml) and di-ethylene glycol (20 ml) is stirred at about 130° C. for 1 hour. The temperature is then slowly raised to 215° C. allowing volatile material to distil off. The stirring at 215° C. is continued for a further 2-3 hours until the nitrogen evolution has ceased. After cooling and dilution with water (30 ml), the resulting solution is acidified with conc. hydrochloric acid (3 ml). The resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from 96% ethanol, 5-amino-4-benzyl-3-benzyloxybenzoic acid is obtained with a melting point of 207.5° -209.5° C.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)C.[BH3-]C#N.[Na+]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC1(F)CCNC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3,3-difluoro-pyrrolidine hydrochloride (2.02 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.02 mmol) and Ti(OiPr)4 (2.42 mmol) in THF is stirred at room temperature for 1 h. To the resulting mixture are added ethanol (3 mL) and NaBH3CN (1.21 mmol). After stirring for 17 h, the reaction is quenched by the addition of sat. aq. NaHCO3 and the resulting precipitate is filtered out. After the filtrate is diluted with AcOEt, the mixture is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-(3,3-difluoro-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester; 1H NMR (CDCl)3 δ: 1.34-1.52 (2H, m), 1.45 (9H, s), 1.79 (2H, bd), 2.19-2.33 (3H, m), 2.78 (2H, dd), 2.83 (2H, dd), 2.95 (2H, dd), 4.00 (2H, bs).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1.[CH3:28][CH2:29][O-:30].[Na+]>C(O)C>[CH2:29]([O:30][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:5]2[S:21][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1)[CH3:28]
Reactant: CC[O-]
Reactant: Cc1nc(-c2ccccc2)nc2sc3c(N4CCNCC4)nc(Cl)nc3c12
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N2CCNCC2)c2sc3nc(-c4ccccc4)nc(C)c3c2n1

Procedure:
1.30 g (3.3 mmol) 2-chloro-9-methyl-4-piperazin-1-yl-7-phenyl-thieno[2,3-d:4,5-d′]di-pyrimidine and 0.67 g (9.9 mmol) sodium ethylate are refluxed in 30 ml ethanol for 3 h. Thereafter, the solvent is removed and the residue is suspended in some water. The aqueous suspension is extracted with dichloromethane and the solvent is removed. 0.90 g (68%) of the title substance is obtained. ESI-MS [m/z]: 407, melting point: >310° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=O)[CH3:12]>C(O)(=O)C.Cl>[CH3:12][C:11]1[NH:1][C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[C:3]=2[N:10]=1
Reactant: CC(=O)Nc1c(C)cc(N)cc1N
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2c(C)cc(N)cc2[nH]1

Procedure:
33.0 g (0.184 mol) N-(2,4-diamino-6-methyl-phenyl)-acetamide were stirred in 400 mL glacial acetic acid for 1.5 h at 100° C. The glacial acetic acid was eliminated i.vac. and the residue remaining was triturated with ether, suction filtered and dried. The free base thus obtained was taken up in methanolic hydrochloric acid and left to stand. The hydrochloride slowly settling out as a precipitate was suction filtered, washed with acetone and dried.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:20])=[C:12]([CH:19]=1)[C:13](N(OC)C)=[O:14].[Cl-].[NH4+]>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:20])=[C:12]([CH:19]=1)[CH:13]=[O:14]
Reactant: CON(C)C(=O)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cc(Br)ccc1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
LiAlH4 (1.47 g, 0.0388 mol) was added little by little to a tetrahydrofuran (108 mL) solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (10.8 g, 0.0388 mol) so that the internal temperature did not exceed −10° C. The reaction mixture was stirred at −15° C. for one hour and carefully added with a saturated ammonium chloride aqueous solution and deposited insolubles were filtered off with celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with 1M hydrochloric acid, a saturated sodium bicarbonate aqueous solution, brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chlorobenzaldehyde (8.1 g, 95%) as a pale yellow crystal. This was used in the next reaction without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccccc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 319(MH+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][CH:44]5[CH2:43][N:48]([CH3:47])[CH2:45]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CN(C)C4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.6-1.87 (m, 7 H) 1.89-1.99 (m, 3 H) 2.29 (s, 3 H) 3.04 (t, J=7.1 Hz, 2 H) 3.27 (s, 3 H) 3.59 (t, J=7.2 Hz, 2 H) 3.64-3.87 (m, 2 H) 3.95 (s, 3 H) 4.29-4.53 (m, 1 H) 4.79 (t, J=8.1 Hz, 1 H) 7.42-7.59 (m, 2 H) 7.82 (s, 1 H) 8.17 (s, 1 H) 8.34 (d, J=8.3 Hz, 1 H) 8.61 (d, J=6.8 Hz, 1 H). [M+H] calc'd for C27H36FN7O3, 526; found 526.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.[OH:19][C:20]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:43][CH:44]([CH3:46])[CH3:45])[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[CH:29][CH:28]=1)([C:23]([F:26])([F:25])[F:24])[C:21]#[CH:22]>[Pd].COCCOC.[Cu]I>[OH:19][C:20]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:43][CH:44]([CH3:46])[CH3:45])[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[CH:29][CH:28]=1)([C:23]([F:26])([F:25])[F:24])[C:21]#[C:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: C#CC(O)(c1ccc(N(CC(C)C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reactant: Brc1ccc2ccccc2c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)CN(c1ccc(C(O)(C#Cc2cccc3ccccc23)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
80.6 mg (0.39 mmol) 2-Bromonaphthalene, 21 mg palladium on carbon (10% Pd), 74.-1 mg (0.39 mmol) copper (I) iodide, and 135 mg (0.98 mmol) K2CO3 were combined 2 mL of DME and 2 mL of water and the resulting mixture was stirred at room temperature for 30 min. A solution of 80 mg (0.2 mmol) of N-[4-(1-hydroxy-1-trifluoromethyl-prop-2-ynyl)-phenyl]-N-isobutyl-benzenesulfonamide (Example 75) in 1 mL of DME was added and the reaction mixture was stirred at 65° C. overnight. The catalyst was removed by filtration over a pad of celite. The filtrate was washed with a saturated aqueous solution of ammonium chloride and brine. The organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc=9:1) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[Br:14][C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Reaction time: 72 h
Yield: 91.7 %

Procedure:
A solution of diethyl methylmalonate (87 g) in absolute ethanol (100 ml) was added to a pre-formed solution of sodium (11.5 g) in ethanol (400 ml) under argon. A hot solution of p-bromobenzylbromide (125 g) in absolute alcohol (200 ml) was added rapidly with vigorous stirring, which was continued for 3 days and the solid so formed was removed by filtration. The filtrate was evaporated and the residue dissolved in ethyl acetate (1 l), washed with brine (250 ml), dried (MgSO4) and evaporated. The residual oil was distilled under vacuum to give diethyl (4-bromophenyl)methylmalonate (150.7 g) b.p. 130-133/0.03 mm Hg; 1H NMR (d6 -DMSO): 1.33 (t, 6 H), 1.4 (s, 3 H), 3.27 (s, 2 H), 4.30 (q, 4 H), 7.23 (d, 2 H), 7.6 (d, 2 H)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1F.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Oc2ccc(I)cc2)c(Cl)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 4-iodophenol (200 mg) in dimethylsulfoxide (1 ml), 218 mg of 2-chloro-1-fluoro-4-(trifluoromethyl)benzene and 251 mg of potassium carbonate were added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was cooled, ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed with water and a saturated saline solution and dried over an anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-80/20)) to afford the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].COCCOC>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: Brc1cccc2c3ccccc3c3nccn3c12
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)c1ccc(-c2cccc3c4ccccc4c4nccn4c23)cc1
Temperature: 80 °C
Yield: 77.7 %

Procedure:
A three neck 1 L round bottom flask was charged with 5-bromo-imidazo[1,2-f]phenanthridine (4.55 g, 15.31 mmole), 4-isopropylphenylboronic acid (3.59 g, 21.89 mmole), potassium carbonate (2N aqueous soln., 27 ml), Pd(OAc)2 (223 mg, 0.99 mmole), triphenylphosphine (1.044 g, 3.98 mmole) and 100 ml of 1,2-dimethoxyethane. The reaction mixture was heated to 80° C. under nitrogen for 17 hrs. The reaction mixture was diluted with methylene chloride and washed by brine. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by chromography on silica gel using hexane/ethyl acetate (80/20) to obtain pure 5-(4-isopropylphenyl)-imidazo[1,2-f]phenanthridine (4 g, 77%).
Reaction SMILES: [CH2:1]([CH:14]1[CH2:18][CH:17]=[CH:16][O:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Br:19][CH2:20][CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([CH:14]1[CH2:18][CH2:17][CH:16]([O:22][CH2:21][CH2:20][Br:19])[O:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCC1CC=CO1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCC1CCC(OCCBr)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2 g (8 mmol) of 2-tridecyl-2,3-dihydrofuran an 1.1 g (8.8 mmol) of 2-bromo-ethanol in 50 ml of carbon tetrachloride were added 20 mg (0.1 mmol) of dry p-toluene-sulphonic acid. After stirring overnight at room temperature, the solvent was evacuated under reduced pressure. The residue was diluted with a aqueous solution of sodium carbonate and extracted with diethyl ether. The organic phase was washed with water and then dryed on anhydrous magnesium sulphate. The solvent was removed by evaporation and the residue was chromatographed on silica gel using 10% by volume diethyl ether in petroleum ether as eluent. This method allowed the recovery, as oils, of first the trans title compound (896 mg) then a mixture of both cis and trans isomers (419 mg) and, finally, the cis isomer (340 mg) as confirmed by their spectral data: NMR (250 MHz, CDCl3, TMS*) δ ##STR25##