Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[NH:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([CH3:18])([C:27]([O:29][CH3:30])=[O:28])[CH3:26])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)C(C)(C)NCCC(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)N(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirred suspension of 2,4-dichloro-5-nitropyrimidine (7.5 g, 38.5 mmol), anhydrous potassium carbonate (10.0 g) in dry acetone (150 mL) was added a solution of methyl 2-methyl-N-(3-methylbutyl)alaninate (5.6 g, 30.0 mmol) in dry acetone (9 mL) at 0° C. The reaction was then allowed to warm up to room temperature and stirred at rt for 16 h. The reaction mixture was filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate-hexane mixture (v:v=5:95)) to give titled product (yield: 15%). 1HNMR (300 MHz, CDCl3): δ 0.85 (s, 3H), 0.88 (s, 3H), 1.30-1.36 (m, 2H), 1.60-1.65 (m, 7H), 3.37-3.42 (m, 2H), 3.72 (s, 3H) and 8.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH2:18][CH3:19])=[C:16]([O:20][CH3:21])[N:15]=[C:14]([O:22][CH3:23])[N:13]=2)C#N)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].CN(C=[O:30])C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH2:18][CH3:19])=[C:16]([O:20][CH3:21])[N:15]=[C:14]([O:22][CH3:23])[N:13]=2)=[O:30])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCc1c(OC)nc(OC)nc1C(C#N)c1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCc1c(OC)nc(OC)nc1C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a stirred solution of (62) (1.97 g, 5.59 mmol) in anhydrous DMF (25 ml) under nitrogen atmosphere, was added 60% sodium hydride (224 mg, 5.59 mmol). After 10 min., oxygen was bubbled into the reaction mixture for 4 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The organic layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, ether:hexanes (1:30)) to afford 1.37 g (72%) of the title compound as a white solid. m.p. 118-119° C.; 1H NMR (200 MHz, CDCl3) δ 1.09 (3H, t, J=7.4 Hz), 2.46 (2H, q, J=7.4 Hz), 3.95 (3H, s), 4.08 (3H, s), 7.58 (1H, t, J=1.8 Hz), 7.56 (2H, d, J=1.8 Hz).
Reaction SMILES: [C:1]([O:7][C:8]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])([CH:10]=[CH2:11])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=C[CH:26]=2)[CH:21]=[CH:20][C:19]=1C(CC([O-])=O)=O>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:5]=1[C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:9])([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:10]=[CH2:11])=[O:6]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Reactant: O=C([O-])CC(=O)c1ccc2ccccc2c1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1

Procedure:
Crude 3,7-dimethyl-1,6-octadien-3-yl 3-oxo-butyrate (154.51, 0.648 mol) from above is placed in a 3000 mL three-necked round-bottomed flask fitted with a condenser, argon inlet, addition funnel, magnetic stirrer and internal thermometer. The contents are dissolved in 350 mL of dichloromethane and treated with powdered calcium hydroxide (50.44 g, 0.681 mol). The mixture is stirred at 30° C. for 30 min and then heated to 40° C. 2-Naphthoyl chloride (142.12 g, 0.746 mol) dissolved in 20 mL of dichloromethane is added dropwise over 15 min. The mixture continues to be heated at this temperature for 1 h. Ammonium chloride (36.41 g, 0.681 mol) dissolved in 250 mL of water is added to the reaction mixture and the pH adjusted to ˜9 with 28% ammonium hydroxide. After stirring 30 min at 35° C. the pH is adjusted to ˜1 with 20% HCl. The mixture is transferred to a separatory fumnel containing diethyl ether (500 mL) and water (500 mL). The layers are separated and the organic phase is washed with saturated NaHCO3 solution (2×500 mL), dried over MgSO4, filtered and concentrated by rotary evaporation to give a yellow red oil. At this point a light yellow solid precipitates from the mixture. An equal volume of hexane is added and the solids is collected by filtration and dried. NMR analysis indicates the solid is 2-naphthoic acid. The eluent is concentrated again by rotary evaporation to give a red oil. The oil is taken up in an equal volume of dichloromethane, passed through a plug of silica gel (400 g) and eluted with dichloromethane. The mixture is concentrated by rotary evaporation and stripped by Kugelrohr distillation (40° C., 0.10 mm Hg, 30 min) to yield 173.26 g (76.3%) of the product as a red oil; this product is a mixture of a 1:10 molar ratio of linalyl acetoacetate to linalyl (2-naphthoylacetate. A portion of this material is purified by column chromatography (elution with 2.5% ethyl acetate in hexanes) to give the desired product as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][S:10]([CH3:12])=O.FC(F)(F)C(O)=O>C1C=CC=CC=1>[CH3:12][S:10][CH:9]1[C:8](=[O:13])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: CS(=O)CC(=O)c1ccccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CSC1Oc2ccccc2C1=O

Procedure:
2-Hydroxy-1-[(methylsulfinyl) acetyl]benzene (1.5 g 0.0075m) and trifluoroacetic acid (1.5 g) are refluxed in benzene (25 ml) for one hour under nitrogen. The solvent is removed under reduced pressure to give a pale yellow oil which crystallizes on standing. Recrystallization from ethanol gave white crystals, (0.611 g 45%), m.p. 81°-82° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26](I)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: c1cocn1
Reactant: CCCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (167 mg, 2.4 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.7 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 7.3 mL, 7.3 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-{[butyl(methyl)amino]carbonyl}-5-iodobenzoate (864 mg, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (112 mg, 0.10 mmol). The reaction mixture is heated at reflux for 1.5 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound. ESI MS m/z 317.1 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]12[N:38]=[CH:37][N:36]=[C:35]1[CH:34]=[N:33][CH:32]=[N:31]2>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]56[N:38]=[CH:37][N:36]=[C:35]5[CH:34]=[N:33][CH:32]=[N:31]6)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Reactant: ClC12N=CN=CC1=NC=N2
Product: C[C@H](Nc1nccc(-n2cnc3cc(C45N=CN=CC4=NC=N5)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 4-chloropurine. Mass spectrum (ESI) 443.4 (M+).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:29]O)[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:29]=[C:23]2[C:22]3[C:26](=[CH:27][C:19]([F:18])=[CH:20][CH:21]=3)[NH:25][C:24]2=[O:28])=[CH:10][C:9]=1[F:15])[CH3:17]
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cc(F)ccc32)cc1F
Yield: 32.4 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (269 mg, 1.5 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (195 mg, 32%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH2:17][C:16]=3[CH:26]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1([CH3:40])[O:39][CH2:38]1>CO>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[CH2:22][CH2:21]4)[CH2:17][C:16]=3[CH:26]=2)=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CC1(C)CO1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CN1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine hydrochloride (100 mg) and N,N-diisopropylethylamine (46 μl) in methanol (5 mL) is stirred for 10 min at room temperature. 1,1-Dimethyloxirane (34 μl) is added and the resulting mixture is heated to 45° C. After the conversion is complete, the solvents are evaporated in vacuo and the crude product is used for the next step without further purification. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1([F:35])[O:28][C:27]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[CH:32][C:26]=2[O:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:35][C:24]1([F:23])[O:28][C:27]2[CH:29]=[CH:30][C:31]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)=[CH:32][C:26]=2[O:25]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)OC(F)(F)O5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To 10 mL of a chloroform solution containing 226 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 150 mg of 2,2-difluorobenzo[1,3]dioxol-5-carbaldehyde, 43 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 257 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=10:1] to give 188 mg of 1-(2-(4-((2,2-difluorobenzo[1,3]dioxol-5-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29].C([O-])(=O)C.[K+].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C.ClCCl>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:29])=[C:2]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[CH:41]=3)[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(-c3cccc(F)c3)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7F (210 mg), potassium acetate (176 mg), 3-fluorobenzeneboronic acid (84 mg), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (12 mg) in DMF (6 mL) was heated at 90° C. for 3 hours then cooled, diluted with dichloromethane, washed with water, and dried (Na2SO4), filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with 0-2% methanol/dichloromethane.
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:28][CH:27]5[CH:25]([CH:26]5[CH2:29][OH:30])[CH2:24]4)=[CH:20][CH:19]=3)[CH:16]=2)[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:35][CH2:34]1.Cl.[NH+]1C=CC=CC=1.C1(O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH:46][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]6[CH:19]=[CH:20][C:21]([CH2:22][N:23]7[CH2:28][CH:27]8[CH:25]([CH:26]8[CH2:29][OH:30])[CH2:24]7)=[CH:31][CH:32]=6)[CH:16]=5)[N:11]=[CH:10][N:9]=4)=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:34][CH2:35]1
Reactant: Nc1ccc2c(ccn2CC2CC2)c1
Reactant: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Oc6ccccc6)c5c4)cc3)CC12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: Oc1ccccc1
Product: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Nc6ccc7c(ccn7CC7CC7)c6)c5c4)cc3)CC12
Temperature: 110 °C
Yield: 66.3 %

Procedure:
To a 3 mL Wheaton vial was added {3-[4-(4-phenoxy-quinazolin-6-yl)-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 16 (100 mg, 0.24 mmol), 1-cyclopropylmethyl-1H-indol-5-ylamine 19 (48 mg, 0.26 mmol), pyridinium hydrochloride (33 mg, 0.284 mmol), and phenol (155 mg, 1.652 mmol). The vial was capped and heated overnight at 110° C. The vial was cooled to room temperature and the residue taken up in CHCl3 and washed with 15% aqueous NaOH, water, brine, and dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (silica gel, EtOAc:MeOH, 95:5) to provide compound 18 (88 mg, 0.159 mmol) as a light brown solid in 67% yield. For compound 18: MS (Cl) m/e 515 (M++1, 100); HPLC, rt=4.83 min.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[Cl:14][C:13]1[CH:12]=[CH:11][C:10]([C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH2:1])=[CH:9][C:8]=1[Cl:7]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(OCC(=O)c2ccc(Cl)c(Cl)c2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(COc1ccc(OC)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (60.3 g) in THF (800 mL) was added potassium tert-butoxide (20.7 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise a solution of 1-(3,4-dichlorophenyl)-2-(4-methoxyphenoxy)ethanone (48 g) in THF (400 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.1 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH:12]([OH:19])[CH2:13][NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[CH2:23]=O>>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]2[O:19][CH2:23][N:14]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:13]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)NCC(O)c1cccc(OCc2ccccc2)c1
Reactant: C=O
Product: CC(C)(C)N1COC(c2cccc(O)c2)C1

Procedure:
In the manner described in Example 28, m-(benzyloxy)-α-[(tert-butylamino)methyl]benzyl alcohol is reacted with formaldehyde to afford the oxazolidine derivative, which is debenzylated by the procedure of Example 26 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: COc1ccc(N(CCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)CNC(=O)CCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-3-(p-anisidino)propionic acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]glycinate (M.P. 87° to 89°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]glycine (M.P. 185° to 187°).
Reaction SMILES: C1C2C(COC(=O)N[C@H](C([N:25]3[C:29]4=[N:30][CH:31]=[C:32](Br)[CH:33]=[C:28]4[C:27]([C@@H:35]([C:37]4[C:42]([Cl:43])=[CH:41][CH:40]=[C:39]([F:44])[C:38]=4[Cl:45])[CH3:36])=[CH:26]3)=O)CC(C)C)C3C(=CC=CC=3)C=2C=CC=1.C(OC([N:54]1[CH2:59][CH2:58][N:57]([C:60](=[O:76])[C:61]2[CH:66]=[CH:65][C:64](B3OC(C)(C)C(C)(C)O3)=[CH:63][CH:62]=2)[CH2:56][CH2:55]1)=O)(C)(C)C>>[Cl:45][C:38]1[C:39]([F:44])=[CH:40][CH:41]=[C:42]([Cl:43])[C:37]=1[C@H:35]([C:27]1[C:28]2[C:29](=[N:30][CH:31]=[C:32]([C:64]3[CH:63]=[CH:62][C:61]([C:60]([N:57]4[CH2:58][CH2:59][NH:54][CH2:55][CH2:56]4)=[O:76])=[CH:66][CH:65]=3)[CH:33]=2)[NH:25][CH:26]=1)[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)n1cc([C@H](C)c2c(Cl)ccc(F)c2Cl)c2cc(Br)cnc21
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3ccc(C(=O)N4CCNCC4)cc3)cc12

Procedure:
Example 69 was synthesized according to Suzuki coupling method described above for synthesis of example 66, using ((S)-1-{5-Bromo-3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methylbutyl)carbamic acid 9H-fluoren-9-ylmethyl ester and 4-[4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester. The crude material was purified by HPLC. MS (ES+): m/z=497.24, 499.25 (100, 69) [MH+]. HPLC: tR=0.72 min (HPLC-ACQUITY, Purity).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].CCO.[BH4-].[Na+].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with compound 10.4 (34.9 g, 95.7 mmol), EtOH (175 mL) and THF (17.5 mL). Next, sodium borohydride (1.10 g, 29.1 mmol) was added in 3 portions at 0° C., and the reaction was vigorously stirred at 0° C. for 1 h. The reaction mixture was poured into 463 mL of 0.25 N HCl at 0° C. and the product was extracted with 3×200 mL of AcOEt. The combined organics were washed sequentially with 2×200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 20% AcOEt/hexane-30% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (33.5 g). 1H NMR (400 MHz) (CDCl3) δ 7.37 (1H, d, J=1.5 Hz); 7.31-7.28 (2H, m); 7.05 (1H, dd, J=1.8, 8.2 Hz); 6.77 (1H, d, J=8.2 Hz); 6.72 (1H, d, J=8.3 Hz); 4.67 (2H, s); 4.61 (2H, d, J=5.9 Hz); 4.28 (2H, q, J=7.2 Hz); 2.29 (3H, s); 1.66 (1H, t, J=5.9 Hz); 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:21](OC)=[O:22])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Br:1][C:2]1[C:3]([CH2:21][OH:22])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CCc1ccc(Cc2cccc3cc(C(=O)OC)c(Br)cc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCc1ccc(Cc2cccc3cc(CO)c(Br)cc23)cc1
Yield: 98.9 %

Procedure:
Under a nitrogen stream, methyl 3-bromo-5-[(4-ethylphenyl)methyl]-2-naphthoate (334.1 mg, 0.87 mmol) was dissolved in diethyl ether (10.0 mL). To the resultant mixture was added lithium aluminum hydride (39.7 mg, 1.04 mmol) under ice-cooling, and the resultant mixture was stirred for 30 minutes. Water was added thereto, and the resultant mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, to thereby obtain the titled compound (305.8 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([Cl:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[CH:3][C:4]=2[Cl:19])[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)c1
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2Cl)c1[N+](=O)[O-]
Yield: 99.6 %

Procedure:
Method H3 was used with 4-(4-amino-2-chlorophenoxy)-3-nitropyridin-2-amine (0.40 g, 1.42 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.32 g, 1.42 mmol) to afford the title compound (0.71 g, 100%). 1H NMR (250 MHz, DMSO-d6) δ 5.86 (d, 1H, J=5.6 Hz), 7.22 (s, 2H), 7.35 (d, 1H, J=8.8 Hz), 7.44 (dd, 1H, Ja=8.8 Hz, Jb=2.4 Hz), 7.60-7.69 (m, 2H), 7.87 (d, 1H, J=2.4 Hz), 7.99 (d, 1H, J=5.7 Hz), 8.10 (d, 1H, J=2.1 Hz), 9.17 (s, 1H), 9.29 (s, 1H). m/z 502.2 [(M+H)+ calcd. for C19H12Cl2F3N5O4 501.0].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8].C(N(CC)CC)C>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:14])([O-:9])=[O:8]
Reactant: Cn1cccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Yield: 45.9 %

Procedure:
A solution of 1-methylpyrrole (10.0 g, 123.0 mmol), 3-nitrobenzoyl chloride (68.47 g, 369 mmol), and triethylamine (17.14 ml, 123 mmol) in xylenes (150 ml) was refluxed for 40 h. Purification of the reaction mixture on a Florisil® column (hexane-acetone, 85:15) gave 2-(3-nitrobenzoyl)-1-methylpyrrole (13.0 g, 46%) as a solid. ##STR43##