Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(C)C=CC=C[CH:8]=1.[C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)#[N:15].Cl[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([OH:37])=[O:36]>O.C(O)C>[C:14]([C:16]1[CH:17]=[C:18]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=2)[C:35]([O:37][CH2:7][CH3:8])=[O:36])[CH:19]=[CH:20][C:21]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)#[N:15]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1ccccc1
Reactant: N#Cc1cc(B(O)O)ccc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccnc(-c2ccc(-c3cccnc3)c(C#N)c2)c1
Temperature: 100 °C

Procedure:
6 ml of aqueous 2 M sodium carbonate solution and 70 mg of tetrakistriphenylphosphine palladium were added to a toluene (15 ml) solution of 450 mg of (3-cyano-4-pyridin-3-ylphenyl)boronic acid and 412 mg of 2-chloroisonicotinic acid, and in an argon atmosphere, this was heated at 100° C. for 2 hours. 3 ml of ethanol was added, followed by further heating at 100° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 93:7) to obtain 127 mg of ethyl 2-(3-cyano-4-pyridin-3-ylphenyl)isonicotinate. F: 330.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[Cl:24][C:25]1[CH:50]=[CH:49][C:28]([CH2:29][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28](/[CH:29]=[CH:18]/[C:17]2[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])[CH:22]=[CH:21][CH:20]=2)=[CH:49][CH:50]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28](/[CH:29]=[CH:18]\[C:17]2[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])[CH:22]=[CH:21][CH:20]=2)=[CH:49][CH:50]=1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2ccc(Cl)cc2)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C\c2ccc(Cl)cc2)c1
Yield: 13 %
Yield: 10 %

Procedure:
Phthalimide 29 was coupled with (4-chlorobenzyl)triphenylphosphonium bromide according to the method used in Example 76. Purification by flash chromatography (7% EtOAc-hexanes) gave (E)-2-(3-(3-(4-chlorostyryl)phenyl)propyl)isoindoline-1,3-dione (0.120 g, 10%) and (Z)-2-(3-(3-(4-chlorostyryl)phenyl)propyl)isoindoline-1,3-dione (0.150 g, 13%) as yellow solids. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.79-7.86 (m, 2H), 7.68-7.73 (m, 3H), 7.12-7.17 (m, 5H), 7.00-7.05 (m, 3H), 6.58 (d, J=12.0 Hz, 1H), 6.50 (d, J=12.0 Hz, 1H), 3.68 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.90-1.97 (m, 2H).
Reaction SMILES: CO.[O:3]=[C:4]([N:18]1[CH2:23][CH2:22][N:21]2[C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=[C:20]2[CH2:19]1)[CH2:5][CH:6]([NH2:17])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16].[C:31]1([CH3:54])[CH:36]=[CH:35][C:34]([C@@:37]([C:51]([OH:53])=[O:52])([OH:50])[C@@:38]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)([OH:42])[C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1>O>[CH:13]1[C:8]([CH2:7][C@@H:6]([NH2:17])[CH2:5][C:4]([N:18]2[CH2:19][C:20]3=[N:26][N:25]=[C:24]([C:27]([F:30])([F:29])[F:28])[N:21]3[CH2:22][CH2:23]2)=[O:3])=[C:9]([F:16])[CH:10]=[C:11]([F:15])[C:12]=1[F:14].[C:31]1([CH3:54])[CH:36]=[CH:35][C:34]([C@@:37]([C:51]([O-:53])=[O:52])([OH:50])[C@@:38]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)([OH:42])[C:39]([O-:41])=[O:40])=[CH:33][CH:32]=1
Reactant: Cc1ccc([C@](O)(C(=O)O)[C@@](O)(C(=O)O)c2ccc(C)cc2)cc1
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: O
Solvent: CO
Product: Cc1ccc([C@](O)(C(=O)[O-])[C@@](O)(C(=O)[O-])c2ccc(C)cc2)cc1
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 24 h
Yield: 66.3 %

Procedure:
A mixture of methanol (390 mL), water (80 mL), 7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (13 g), and di-p-tolyl-L-tartaric acid (13 g) is stirred for about 24 hours. The separated solid is filtered off, washed with ethanol (15 mL) and dried at about 45° C. to afford the title compound. (Yield: 66.3%; purity by HPLC: 99.93%)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
In the drybox, 14.4 mg (0.087 mmol) of (Me3C)2PH(O) from Experiment 2, 20.0 mg (0.0218 mmol) of Pd2 (dba)3 and 4.0 mL of 1,4-dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 651 mg (2.0 MnMol) of CsCO3 and 146.3 mg (1.2 mm) of PhB(OH)2 were added into the mixture above, followed by syringing 122 μl (1.2 mmol) of PhCl into the reactor. The resulting mixture was refluxed for 24 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 163 mg (88% yield) of biphenyl. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J=7.75 Hz, 4H), 7.60 (t, J=7.65 Hz, 4H), 7.50 (t, J=7.38 Hz, 2H).ppm. 13C NMR (125 MHz, CDCl3): δ 141.2, 128.7, 127.2, 127.1 ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CCNCC1
Reactant: Cc1ccc2c(c1)CCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3cc(C)ccc32)CC1
Reaction time: 20 h
Yield: 47.7 %

Procedure:
A 4 mL vial was charged with crude 1-(3-chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH14) (0.128 g), 4-butylpiperidine (0.076 g, 0.54 mmol), KI (0.166 g, 1.00 mmol), and K2CO3 (0.138 g, 1.00 mmol) in MeCN (2 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-1) (0.088 g, total yield 41%). 1H NMR (CD3OD) d 7.07-7.01 (m, 3H), 3.94 (t, J=7.4 Hz, CH2), 2.90-2.80 (m, 4H), 2.57-2.53 (m, 2H), 2.39-2.33 (m, 2H), 2.27 (s, 3H, CH3), 1.95-1.90 (m, 2H), 1.85-1.79 (m, 2H), 1.66 (d, J=9.8 Hz, 2H), 1.30-1.17 (m, 9H), 0.89 (t, J=6.8 Hz, CH3); 13C NMR (CD3OD) d 172.4, 137.9, 134.1, 129.8, 129.0, 128.0, 116.3, 57.1, 55.0, 41.3, 37.4, 36.8, 33.1, 32.8, 30.1, 26.2, 25.5, 23.9, 20.7, 14.4; HPLC-MS (ammonium acetate) [M+H+]=343.33.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12]OC(C)(C)C>C(Cl)Cl.C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([NH2:11])=[CH:3][C:2]=1[F:1]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CC(C)(C)OCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cc(F)c(Cl)cc1C(=O)O
Reaction time: 1.5 h
Yield: 111.2 %

Procedure:
To a solution of 4-fluoroanthranilic acid (0.882 g, 5.69 mmol) in methylene chloride (50 ML) and acetic acid (10 mL) is added tert-butyl hypochlorite (0.71 mL, 6.25 mmol) solution in dichloromethane (1 mL) dropwise over 1 minute. After 90 minutes, the reaction mixture is washed with water and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated to afford 5-chloro-4-fluoroanthranilic acid (1.20 g). MS CI: m/e 188 (M+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:21][C:22]#[N:23]>O>[CH:4]1[CH:5]=[C:21]2[C:22]([NH2:23])=[C:8]3[C:3](=[N:2][C:7]2=[CH:8][CH:3]=1)[CH:4]=[CH:5][CH:6]=[CH:7]3
Reactant: CC#N
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: Nc1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl (1.0 g) was dissolved in CH3CN (50 ml). To the suspension was added aniline (0.42 g) in CH3CN (10 ml), followed by water (50 ml). The solution was stirred at room temperature for 2 hours, but the solution did not become homogeneous. The solution was heated for 1 hour and then cooled to room temperature. To the solution was added ammonium persulphate (1.2 g) in water (10 ml) and the resulting mixture was stirred for 20 hours.
Reaction SMILES: [OH-].[K+].CS(C)=O.[NH:7]1[CH:11]=[N:10][N:9]=[N:8]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=2[S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[CH:16][CH:15]=1>O>[CH2:25]([C:23]1[S:22][C:21]([S:29]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])(=[O:30])=[O:31])=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:8]3[N:9]=[N:10][CH:11]=[N:7]3)=[CH:19][CH:18]=2)[CH:24]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: c1nnn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
KOH (112.2 mg, 2.00 mmol, crushed pellets) was added to DMSO (10 mL, dried over 4 A molecular sieve) and stirred for 5 min. Tetrazole (28.0 mg, 0.4 mmol) was added to the mixture, which was then stirred for 2 h. 3-(4-Bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (130 mg, 0.292 mmol, see step (b) above) was added, the mixture was cooled briefly and stirred for an additional hour before water (50 mL) was added. The reaction mixture was extracted with ethyl acetate (250 mL) and the extract was washed with water (2×50 mL) and brine (0 mL). The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified on column chromatography using hexane:acetone (3:1) as eluent to give the sub-title compound (28.6 mg, 0.066 mmol, 23% yield).
Reaction SMILES: C([Li])CCC.CC(NC(C)C)C.[CH3:13][N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15]1.[C:23]1([CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32][CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:13][N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[C:33]1([OH:37])[CH2:34][CH2:35][CH2:36][N:30]([CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32]1
Reactant: Cn1cnc2ncccc21
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2(O)CCCN(Cc3ccccc3)CC2)nc2ncccc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
n-Butyllithium (1.6M in hexanes, 0.164 mol) was added dropwise at −30° C. under N2 flow to a mixture of N-(1-methylethyl)-2-propanamine (0.164 mol) in THF (70 ml). The mixture was cooled to −70° C. A mixture of 1-methyl-1H-imidazo[4,5-b]pyridine (0.0751 mol) in THF (70 ml) was added dropwise. The mixture was stirred for 1 hour. A mixture of hexahydro-1-(phenylmethyl)-4H-azepin-4-one (0.0787 mol) in THF (60 ml) was added at −70° C. The mixture was stirred at −70° C. for 2 hours, brought to 0° C., poured out into water and NH4Cl and extracted with DCM and a small amount of methanol. The organic layer was separated, dried, filtered and evaporated to dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5). The desired fractions were collected and the solvent was evaporated, yielding 8.8 g of (±)-hexahydro-4-(1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-1-(phenylmethyl)-1H-azepin-4-ol (compound 152).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(N(CC)CC)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[C:18]([NH:22][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccnc(C(=O)O)c1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccnc(C(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
4-Methylpyridine-2-carboxylic acid (500 mg, 3.65 mmol), triethylamine (1.27 g, 12.5 mmol, 1.75 mL) and tert-butylamine (267 mg, 3.65 mmol) were combined and stirred in dichloromethane (1 mL). 1-Propanephosphonic acid cyclic anhydride (4.82 g, 7.5 mmol, 4.5 mL, 50% solution in ethyl acetate) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure and the resulting residue taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the title compound (376 mg). MS (ESI) m/z 193.4 [M+H]+
Reaction SMILES: [CH2:1]([N:8]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][CH:10]([OH:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:14]=1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>C(O)(C)C.O>[CH2:1]([N:8]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][CH:10]([OH:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:27]([O:29][CH3:30])=[O:28])[C:14]=1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc(N)c1O
Reactant: COC(=O)Cl
Solvent: CC(C)O
Solvent: O
Product: COC(=O)Nc1cccc(OCC(O)CN(Cc2ccccc2)C(C)(C)C)c1O

Procedure:
14.5 g of 1-(N-benzyl-tert.-butylamino)-3-(3-amino-2-hydroxy-phenoxy)-2-propanol are dissolved in 140 ml of an isopropanol/water mixture (1:1) and 5.0 ml of methyl chloroformate are added, at 15°-20°, whilst stirring vigorously and stirring is continued for a further 11/2 hours at room temperature, the reaction mixture is then evaporated and the residue is dissolved in 50 ml of water. After extraction with 20 ml of ethyl acetate, the acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and extracted with 3 times 100 ml of methylene chloride. Evaporation of the organic phase gives the crude base, from which crystalline 1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-methoxycarbonylamino-phenoxy)-2-propanol with a melting point of 130°-133° is isolated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:24](O)=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][C:41]([NH:40][C:24](=[O:25])[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Oc2ccccc2)c1)C(=O)O
Reactant: Nc1ccncn1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ccncn1
Reaction time: 0.5 h
Yield: 136.8 %

Procedure:
N-(t-butoxycarbonyl)-3-phenoxyphenylalanine (1 g) was dissolved in dry tetrahydrofuran (30 ml) and triethylamine (2 ml) was added thereto. Thereafter, ethyl chlorocarbonate (0.3 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution, 4-aminopyrimidine (0.24 g) was added, followed by stirring at room temperature for 10 hours. After distilling off the solvent, the residue was extracted with ethyl acetate, followed by washing with water. After drying, the solvent was distilled off to obtain N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine 4-pyrimidylamide (I) (1.5 g), which was confirmed as a substantially pure product by an NMR analysis, in the form of a white powder.
Reaction SMILES: OCC[N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[C:10]1[CH:23]=[C:22](C)[C:21]2[C:20](=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:26])[C:12]=2[C:11]=1[CH3:27].C(N(C(C)C)C(C)C)C.C([N:40](C(C)C)[P:41](Cl)(C)=[O:42])(C)C.C([O:50]C(=O)C)C>C(Cl)Cl>[CH3:5][C:10]1[CH:23]=[CH:22][C:21]2[C:20](=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:26])[C:12]=2[C:11]=1[CH3:27].[P:41]([NH2:40])([O-:42])[O:50][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C2CNCCN2CCO)c(C)c2c1C(=O)c1ccccc1C2=O
Reactant: CC(C)N(C(C)C)P(C)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1C)C(=O)c1ccccc1C2=O
Product: NP([O-])ON1CCNCC1
Reaction time: 0.5 h

Procedure:
1-(1-[2-hydroxyethyl)piperazinyl-1,4-dimethylanthraquinone (1 mmol) is dissolved in CH2Cl2 (2 mL), and N-ethyldiisopropylamine (760 μL, 4 mmol) and N,N-diisopropylmethylphosphonamidic chloride (194 μL, 1 mmol) are added. After 30 min., the solution is poured into ethylacetate (5 mL, previously washed with 2×5 mL of 5% NaHCO3, and 2×5 mL of saturated NaCl). The ethylacetate phase is dried over Na2SO4 and evaporated to an oil, N-1,4-dimethylanthraquinonyl-O-methoxydiisopropylamino phosphite 1-(2-hydroxyethyl)piperazine.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)#[CH:18]>>[NH2:23][C:22]1[CH:24]=[CH:25][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccc(N)cc1
Product: Nc1ccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Yield: 85.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 4-ethynylaniline (76 mg, 0.65 mmol) to provide 261 (115 mg, 85% yield) as a brown solid. LC-MS (M+H=312 obsd.=312).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[O:8][CH2:9][C:4]=2[CH:3]=1.[H][H].C(=O)([O-])[O-].[K+].[K+].NC1C=CC=CC=1.[F:36][C:37]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:38]=1[C:39]([N:41]=[C:42]=[O:43])=[O:40]>C1(C)C=CC=CC=1.[Pt]>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:42]([NH:41][C:39](=[O:40])[C:38]4[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:37]=4[F:36])=[O:43])=[CH:12][CH:11]=3)[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2OCc3cc(Br)ccc3O2)cc1
Agent: [Pt]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(C2OCc3cc(Br)ccc3O2)cc1
Temperature: 60 °C

Procedure:
A suspension of 6-bromo-2-(4-nitrophenyl)-1,3-benzodioxan (2.05 g) in toluene (150 ml) was hydrogenated at ≤60 psi hydrogen pressure in the presence of 5% platinum/charcoal (0.5 g) and anhydrous potassium carbonate (0.5 g) at ambient temperature. The reaction mixture was filtered and evaporated under reduced pressure, azeotropically removing the water formed in the reaction. The resulting crude aniline derivative was redissolved in dry toluene (25 ml) and treated with 2,6-difluorobenzoyl isocyanate (1.2 g), warming briefly to approx. 60° C. then allowing the stirred reaction mixture to cool overnight. Cooling to 0°-5° C. afforded a precipitate of impure product which was purified by crystallisation from ethanol (0.52 g, 17%), mp 194°-195° C.
Reaction SMILES: CI.[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([OH:14])=[CH:11]2)=[CH:6][CH:5]=1.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH:13]=1
Reactant: Oc1ccc2ccc(Br)cc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2ccc(Br)cc2c1
Reaction time: 72 h
Yield: 96.6 %

Procedure:
Methyl iodide (2 mL, 32.1 mmol) was added to a mixture of 7-bromonaphthalen-2-ol (6.26 g, 28.0 mmol) and K2CO3 (4.62 g, 33.4 mmol) in DMF (21 mL). After stirring for 3 days, the mixture was partitioned between ethyl acetate/H2O and the organic solution was further washed with H2O (5×60 mL). The organic solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (6.41 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27].O>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]([NH:1][C:26](=[O:27])[C:25]([Cl:30])([Cl:29])[Cl:24])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 23.2 g (100 mmol) of 2-amino-5-chlorobenzophenone and 11 g (110 mmol) of triethylamine in 200 mL of tetrahydrofuran was added dropwise 20 g (110 mmol) of trichloroacetyl chloride at temperature of 5° C. to 15° C. After being stirred for 3 hours at ambient temperature, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on anhydrous sodium sulfate and concentrated in vacuo. The resulting crude crystals were recrystallized from ethanol to give 33.8 g (89.9 mmol) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([CH:15]3[CH2:14][N:13]([C:26]4[N:27]=[CH:28][CH:29]=[CH:30][N:31]=4)[CH:10]4[CH2:11][CH2:12][NH:8][CH:9]34)=[CH:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2c(C3CN(c4ncccn4)C4CCNC34)c[nH]c2c1
Reaction time: 2.5 h
Yield: 94.7 %

Procedure:
To a solution containing 70 (210 mg, 0.49 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 2.5 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 150 mg (93%) of 71 which was used without further purification. Mass spectrum, m/z [324] (M+H)+.