Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:30])[CH3:29].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:30][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)c1ccc(F)cc1-c1ccc(F)cc1F
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2ccc(F)cc2F)cc1
Yield: 69.8 %

Procedure:
The title compound was prepared from 4-methoxybenzenesulfonyl chloride (146 mg, 0.7 mmol), 1-(-2′,4′,5-trifluoro-1,1′-biphenyl-2-yl)ethylamine (169 mg, 0.67 mmol), and triethylamine (187 μL, 1.3 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (197 mg, 70%) as a white solid;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][C:19]1[CH:27]=[C:26]([O:28]C)[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:17][CH2:18][C:19]4[C:20](=[CH:24][CH:25]=[C:26]([OH:28])[CH:27]=4)[C:21]3=[O:22])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: COc1ccc(C(=O)Cl)c(CCCl)c1
Product: CN(C)C1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2)C1

Procedure:
According to Method A, [1-(4-amino-phenyl)-pyrrolidin-3-yl]-dimethylamine was reacted with 2-(2-chloroethyl)-4-methoxy-benzoyl chloride. The dihydroisoquinolinone thus obtained was treated with hydrogen bromide according to Method L. In this way the product was obtained with molecular weight 351.45 (C21H25N3O2); MS (ESI): 352 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[NH:18][C:17](=O)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccncc1
Reactant: O=c1[nH]c(-c2cccc(C(F)(F)F)c2)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: FC(F)(F)c1cccc(-c2nc(Nc3ccncc3)c3nccnc3n2)c1

Procedure:
The title product was synthesized by reaction of the 2-(3-trifluoromethylphenyl)-pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19]C)[CH:3]=1.[OH-].[Na+]>C(O)C(O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([OH:19])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Yield: 32.5 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)-ethyl]-2-methoxybenzamide (29.5 g, 0.1 mole), sodium hydroxide pellets (4.0 g, 0.1 mole) and 1,2-propanediol (70 ml) was stirred and heated under reflux for 20 hours followed by concentration in vacuo. The residue was treated with 1N HCl (100 ml) and again concentrated in vacuo. The residue was chromatographed on silica using methylene chloride (90), methanol (10), ammonia (0.5) solvent system. The appropriate fractions were combined and concentrated in vacuo and the residue crystallized from ether to give 9.3 g of product. This was dissolved in hot water, and the solution filtered over charcoal. The filtrate was cooled and filtered to give 6.7 g of tan colored title compound, mp 126°-7° (U.S. Pat. No. 3,357,978 reports mp 160°).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2cccs2)cc1

Procedure:
p-Bromoanisole and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(4-methoxyphenyl)thiophene as a pale yellow solid. APCI-Mass m/Z 191 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[CH3:2]>CCOC(C)=O.[Pt]>[CH2:1]([C:3]1[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:25][CH2:26]3)[CH2:17][CH2:16]2)=[CH:5][C:6]([O:12][CH2:13][CH3:14])=[C:7]([CH:8]=1)[NH2:9])[CH3:2]
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.9 %

Procedure:
A mixture of 1-{1-[2-ethyl-5-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (0.511 g, 1.160 mmol) and sulfided platinum on carbon (0.181 g, 0.046 mmol) in EtOAc (30 mL) was sealed in a round bottom flask with a rubber septum. The reaction mixture was purged with N2 gas and then a balloon of H2 gas was connected and the vessel was flushed with the H2 gas. The reaction was stirred at rt for 48 h. TLC analysis showed the complete consumption of the starting nitro compound so the reaction vessel was purged with N2 and the reaction mixture was filtered through celite to remove the catalyst. The filtrate was concentrated onto silica gel and purified by flash chromatography to afford 5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.452 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.58 (s, 1H), 6.47 (s, 1H), 4.33 (br. s., 2H), 3.94 (q, J=6.93 Hz, 2H), 3.04-3.15 (m, 4H), 2.79-2.93 (m, 5H), 2.54-2.66 (m, 6H), 2.28-2.40 (m, 1H), 1.72-1.85 (m, 2H), 1.45-1.61 (m, 2H), 1.30 (t, J=6.92 Hz, 3H), 1.09 (t, J=7.51 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=2)[C:22](Cl)=[O:23])[CH:12]=[CH:13][CH:14]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][C:29]=1[CH3:40]>ClCCl.C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([C:22]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][C:29]=3[CH3:40])=[O:23])[CH:25]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (74 ul, 0.53 mmol, 1.5 eq) was added to a suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoylchloride (105 mgs, 0.36 mmol) and ethyl (4-amino-3-methylphenyl)acetate (103 mg, 0.53 mmol, 1.5 eq) in dichloromethane (5 ml). The mixture was stirred at room temperature overnight. The mixture was then diluted with acetonitrile and purified by SCX cartridge (5 g) eluting with acetonitrile. Fractions containing product were combined and evaporated to give the title compound as a yellow gum, 174 mg. MS (ES+) m/z 452 [M+H]+ (C26H2635ClNO4).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[C:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21](OC)=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1.Cl.[NH2:31][C@H:32]1[CH2:37][C@@H:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=2[F:46])[C@@H:35]([CH3:47])[N:34]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:33]1=[O:53].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:26][N:10]1[C@:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([NH:31][C@H:32]4[CH2:37][C@@H:36]([C:38]5[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:39]=5[F:46])[C@@H:35]([CH3:47])[N:34]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:33]4=[O:53])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]
Reactant: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](N)C(=O)N1CC(F)(F)F
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)NC(=O)N2C)C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylic acid (described in Intermediate 1, 20 mg, 0.077 mmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride (described in Intermediate 5, 22 mg, 0.058 mmol), HOBT (12 mg, 0.078 mmol), and EDC (15 mg, 0.078 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.031 mL, 0.175 mmol), and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:NH4OH 100:0:0 to 90:10:1, to give the desired product as a mixture of isomers. Separation of the stereoisomers was achieved by SFC using a ChiralPak IC column, eluting with CO2:MeOH:Et2NH—75:25:0.1, to give (6S)-3′-methyl-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxamide, which was the first major peak to elute, and the title compound, which was the second major peak to elute. HRMS: m/z=584.1715 (M+1), calculated m/z=584.1727 for C26H24F6N5O4. 1H NMR (500 MHz, CD3OD) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.28 (qd, 1H, J=9.0, 4.6 Hz), 7.02 (m, 1H), 4.79 (m, 1H), 4.54 (dd, 1H, J=11.7, 6.8 Hz), 4.02 (m, 1H), 3.93 (m, 1H), 3.68 (dq, 1H, J=15.4, 8.8 Hz), 3.55 (d, 1H, J=18.1 Hz), 3.54 (d, 1H, J=17.6 Hz), 3.40 (d, 2H, J=17.8 Hz), 3.20 (m, 1H), 2.72 (s, 3H), 2.34 (m, 1H), 1.33 (d, 3H, J=6.4 Hz).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.[N+](C1C=C(S(O[CH2:46][C@H:47]2[CH2:49][O:48]2)(=O)=O)C=CC=1)([O-])=O>>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:46][C@H:47]4[CH2:49][O:48]4)[CH3:21])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2CO2)c1=O

Procedure:
Prepared from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 252j) and (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate, using a similar method to that described in Example 299a.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:72])[CH3:71])=[CH:66][CH:65]=1>>[C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)(=[O:72])[CH3:71]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.17 g, 0.71 mmol), then reacted with 1-(4-aminophenyl)ethanone (Aldrich) (0.058 g, 0.43 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetyl-phenyl)-amide as a yellow solid (Yield 0.078 g, 38%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)OCc1ccccc1

Procedure:
3.58 moles (536 ml) of benzyl chloroformate (95%) are added in the course of 45 minutes to 3.25 moles (500 g) of 2-amino-5-nitrophenol and 204.5 g of calcium carbonate in 1.5 liter of dioxane brought to 70° C., the temperature being maintained at between 70° C. and 80° C. When the addition is complete, heating is maintained for a further 30 minutes. The inorganic salts present in the reaction medium are removed by filtration while hot. After the addition of ice-cold water to the filtrate, the expected product crystallizes. After filtration and drying, the product obtained is recrystallized from acetic acid. It melts at 200° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:33]=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:33]=[CH:32][C:13]2[N:14]=[C:15]([C:17]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(=O)OC(C)(C)C)cc3)oc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(=O)O)cc3)oc2c1

Procedure:
20 mg (44 μmol) tert-butyl {4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenoxy}-acetate (Example 66), 500 μl TFA and 1 ml DCM are stirred together for 2 h at RT, then the solv. is totally eliminated i.V. and the residue is crystallised from cyclohexane/EA.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][CH3:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH2:31]([O:33][C:34]1[CH:46]=[CH:45][C:37]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:36][CH:35]=1)[CH3:32]>>[CH3:1][N:2]([CH3:30])[C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]([CH2:27][CH3:28])[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:18]=3)([N:38]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH2:31][CH3:32])=[CH:46][CH:45]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:9][C:8]2=[O:10])=[CH:5][CH:4]=1
Reactant: CCOc1ccc(Nc2ccccc2)cc1
Reactant: CCN(Cc1ccccc1)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Product: CCOc1ccc(N(c2ccccc2)C2(c3ccc(N(CC)Cc4ccccc4)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Yield: 50.5 %

Procedure:
Following a procedure similar to that described in Example 4 but employing 4.0 g of 5-(dimethylamino)-2-[4-(ethylbenzylamino)benzoyl]benzoic acid and 2.2 g of 4-ethoxy-N-phenylaniline there was obtained 3.0 g of 6-(dimethylamino)-3-[4-(ethylbenzylamino)phenyl]-3-[(4-ethoxyphenyl)phenylamino]phthalide, m.p. 148°-152° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange-colored image which changed to green on clay after fluorescent light exposure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=3[CH3:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:41]([O:43][P:44]([CH2:49]OS(C(F)(F)F)(=O)=O)([O:46][CH2:47][CH3:48])=[O:45])[CH3:42]>CN(C)C(=O)C>[CH2:41]([O:43][P:44]([CH2:49][NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=3[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=2)=[C:25]([CH3:31])[CH:26]=1)(=[O:45])[O:46][CH2:47][CH3:48])[CH3:42]
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOP(=O)(CNc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1)OCC
Temperature: 50 °C
Yield: 98.1 %

Procedure:
To a mixture of {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 58.0 μmol), as prepared according to the procedure of step b of Example 120, cesium carbonate (19 mg, 58 μmol), and N,N-dimethylacetamide (0.4 mL) was added a solution of trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) (Xu, Y. et al, J. Org. Chem. 61, 7697 (1996); Phillion, D. et al, Tetrahedron Lett. 27, 1477 (1986)), and heated at 50° C. for 48 h. Additional trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) was added. The mixture was heated at 50° C. for additional 24 h. Solvent was evaporated. The resulting mixture was partitioned between DCM and H2O. Aqueous layer was separated and extracted with DCM. All the DCM layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (20 and 30%) to give the title compound (38 mg, 98% yield) as an orange oil. 1H NMR (CDCl3): δ 8.23 (s, 1H), 7.92–7.88 (m, 2H), 7.53–7.46 (m, 2H), 6.98 (d, 1H, J=8.0 Hz), 6.56–6.53 (m, 2H), 4.23–4.15 (m, 4H), 3.56 (d, 2H, J=12.5 Hz), 2.43 (S, 3H), 2.16 (S, 3H), 1.52 (S, 9H), 1.35 (t, 6H, J=7.0 Hz). ESI-MS (m/z): Cald. For C29H39N3O7PS3: 668.2 (M+H); found: 667.8.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:33]([O:34][CH3:35])[CH3:32])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)cc1Nc1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1F
Reaction time: 1 h
Yield: 85.2 %

Procedure:
In a 500 mL round bottom flask, 4-fluoro-2-(2-fluoro-phenylamino)-benzoic acid (6.0 g, 24.1 mmol), O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU) (18.5 g, 48 mmol) and triethylamine (20 mL, 144 mmol) were added to DMF (80.0 mL). The reaction mixture was stirred for 1 hr. at room temperature, then N,O-dimethylhydroxylamine hydrochloride (4.7 g, 48 mmol) was added. The mixture was stirred for 2 hr. The reaction mixture was poured into 300 mL of ethyl acetate and washed with saturated ammonium chloride (2×150 mL), water (2×200 mL) and brine (1×200 mL). The organic layer was evaporated and purified by flash chromatography using 30% ethyl acetate-hexanes to give 4-fluoro-2-(2-fluoro-phenylamino)-N-methoxy-N-methyl-benzamide (6.0 g, 85.3%).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][NH:4]1.C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29]I)=[CH:19][CH:18]=1>C(#N)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][N:4]2[CH2:5][CH2:6][C:7](=[O:9])[CH2:8][C@@H:3]2[CH3:2])=[CH:21][CH:22]=1
Reactant: C[C@H]1CC(=O)CCN1
Reactant: Clc1ccc(-c2ccccc2CI)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CC(=O)CCN1Cc1ccccc1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
(S)-2-Methyl-piperidin-4-one hydrochloride (100 mg, 0.67 mmol) was combined with K2CO3 (554 mg, 4.0 mmol) in acetonitrile (5.0 mL) and stirred for 15 minutes. 4′-Chloro-2-(iodomethyl)biphenyl (220 mg, 0.668 mmol) was added, and the resulting mixture was heated to 70° C. and stirred for 16 hours. The reaction was cooled to room temperature, filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (heptanes/EtOAc gradient) to afford the title compound as an off-white solid (178 mg, 85% yield). MS (ESI) m/e (M+H+): 313.8
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][C:29]([CH2:35][OH:36])([CH2:32][CH2:33][OH:34])[CH2:30][OH:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[C:41](=[O:43])[CH3:42])(=O)C>N1C=CC=CC=1>[C:19]([O:31][CH2:30][C:29]([CH2:28][CH2:27][C:21]1([CH2:20][CH2:19][O:1][Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([CH2:32][CH2:33][O:34][C:41](=[O:43])[CH3:42])[CH2:35][O:36][C:30](=[O:31])[CH3:29])(=[O:1])[CH3:20]
Reactant: CC(C)(C)[Si](OCCC1(CCC(CO)(CO)CCO)CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCC(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethyl]-2-hydroxymethylbutan-1,4-diol (300 mg) in pyridine (5.0 mL) was added acetic anhydride (5.0 mL) at room temperature. After stirring the solution at room temperature for 16 hours, it was concentrated under reduced pressure to give the title compound (340 mg).