Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:17](O)[C:18]([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:6]
Reactant: CC(C)(C)CO
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)COC(=O)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
2-Chloroisonicotinic acid (2.0 g, 13 mmol) was suspended in 50 mL dry CH2Cl2 and treated with oxalyl chloride (3.5 mL, 5.0 g, 39 mmol) plus 3 drops DMF. The mixture was stirred for 4 h, the volatiles removed in vacuo and the residue taken up in 50 mL CH2Cl2. After cooling to 0° C. and treating with neopentyl alcohol (1.7 ml, 1.4 g, 16 mmol), Et3N (2.5 mL, 1.8 g, 18 mmol) was added in portions. The mixture was warmed to 25° C., stirred for 15 h, washed sequentially with 15 mL H2O, 15 mL saturated aqueous NaHCO3, and 15 mL brine, then dried (Na2SO4), filtered, and concentrated in vacuo to give 2.4 g (80%) of 2-chloroisonicotinic acid, 2,2-dimethyl-propyl ester as an oil, used without additional purification: 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.78 (d J=5.0 Hz, 1H), 4.06 (s, 2H), 1.05 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:22].[CH3:23][O:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][O:24][C:25]1[C:30]([C:2]2[C:3]([CH3:22])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[N:7]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1ncccc1B(O)O
Reactant: COc1ccc(C2(C(=O)Nc3ccc(C)c(Cl)n3)CC2)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4cccnc4OC)n3)CC2)cc1
Temperature: 80 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(4-methoxyphenyl)cyclopropane carboxamide (63 mg, 0.20 mmol) was dissolved in 1,2-dimethoxyethane (2.0 mL) in a reaction tube. 2-Methoxypyridin-3-ylboronic acid (46 mg, 0.30 mmol), aqueous 2 M sodium carbonate (0.20 mL), and (Ph3P)4Pd (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. under N2 atmosphere for 18 hours. Since the reaction was incomplete, it was re-treated with same amount of boronic acid, base and Pd catalyst and was heated at 80° C. for 18 hours. The resulting material was cooled to room temperature, filtered, and evaporated under reduced pressure. The crude product was dissolved in DMSO (2 mL), filtered and purified by reverse phase preparative HPLC to yield N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropane carboxamide. ESI-MS m/z calc. 389.2. found 390.5 (M+1)+. Retention time 1.76 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[CH:25][C:18]=34)=[C:12]([F:26])[CH:11]=2)[CH:3]=1.C(N(C(C)C)C(C)C)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CN(C=O)C>C(C(CCCC)CO)C>[F:26][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:3]=[C:2]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:7]=[C:6]([NH2:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[CH:25][C:18]=12
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCC(CC)CO
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(N2CCOCC2)n1
Temperature: 150 °C

Procedure:
52 mg (0.14 mmol) of 6-chloro-N4-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]pyrimidine-2,4-diamine (from example 60) are dissolved in 2.5 ml of 2-ethylhexanol. 0.24 ml of N-ethyldiisopropylamine and 36 mg (0.42 mmol) of morpholine are added, and the mixture is heated at 150° C. bath temperature for 20 hours. After cooling, a little DMF is added and the mixture is chromatographed on silica gel 60 (gradient column: mobile phase: DCM:methanol=50:1, then 3:1). This gives an oil which is purified by preparative HPLC.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:25]=2)=[C:19]([O:36][CH3:37])[CH:18]=1>C(#N)C>[NH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:31][CH2:32][N:33]([CH2:14][CH:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[CH2:34][CH2:35]3)[N:25]=2)=[C:19]([O:36][CH3:37])[CH:18]=1
Reactant: COc1cc(N)c(Cl)cc1-c1nn(C2CCNCC2)c(=O)o1
Reactant: BrCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(N)c(Cl)cc1-c1nn(C2CCN(CC3CCCCC3)CC2)c(=O)o1
Temperature: 70 °C
Reaction time: 48 h
Yield: 47.8 %

Procedure:
2.01 ml (13.92 mmol) of triethylamine and then 0.92 g (5.2 mmol) of cyclohexylmethyl bromide in 5 ml of acetonitrile are successively added at room temperature, under an argon atmosphere and with magnetic stirring, to a solution of 1.13 g (3.48 mmol) of 5-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one in 40 ml of acetonitrile and the mixture is stirred at 70° C. for 2 days. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform, the solution is washed a number of times with water and dried, the solvent is evaporated under reduced pressure and the residue is crystallized from acetone. 0.7 g of white solid is obtained. Melting point: 186.5-186.7° C.
Reaction SMILES: [F:1][CH:2]([CH3:25])[CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=O)[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:59]([CH2:61][NH2:62])[OH:60]>CN(C=O)C>[F:1][CH:2]([CH3:25])[CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([NH:62][CH2:61][CH2:59][OH:60])=[O:24])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: NCCO
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OCC(C)F)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCO)sc2ncnc(Nc3cccnc3OCC(C)F)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-(2-Fluoropropoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (36.2 mg), HATU (42 mg) and Hünig's base (34 μl) were dissolved in DMF (2 ml) and ethanolamine (9 μl) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was purified directly by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:37])=[C:31]([CH:35]=[CH2:36])[C:32]=3[F:34])[C:27](=[O:38])[C:26]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25]2)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:13][C:10]1[N:9]=[C:8]([NH2:14])[C:7]([CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:17]([O:18][CH3:19])=[C:16](/[CH:36]=[CH:35]/[C:31]3[C:32]([F:34])=[C:33]4[C:28]([C:27](=[O:38])[C:26]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:25][N:24]4[CH:21]4[CH2:23][CH2:22]4)=[CH:29][C:30]=3[F:37])[CH:15]=2)=[CH:12][N:11]=1
Reactant: C=Cc1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1F
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(/C=C/c3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of 193 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)-pyrimidine-2,4-diamine, 224 mg of ethyl 1-cyclopropyl-6,8-difluoro-7-vinyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (J. Heterocyclic Chem., 28, 1581 (1991)), 26 mg of triphenylphosphine, 0.084 ml of triethylamine and 11.2 mg of palladium acetate in 2 ml of dimethylformamide is heated at 100° for 5 hrs. The reaction mixture is cooled to room temperature, poured into 50 ml of water and extracted twice with 25 ml of ethyl acetate each time. The organic phases are washed twice with 25 ml of 2N aqueous hydrochloric acid each time. The hydrochloric acid phases are made basic with sodium bicarbonate and extracted three times with 25 ml of methylene chloride each time. The combined organic phases are washed with 25 ml of water, dried over magnesium sulphate and concentrated. The crude product is recrystallized from methylene chloride/diethyl ether. 140 mg (49%) of ethyl (E)-7-[2-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-vinyl]-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a yellowish solid. Mass spectrum (ISP): 578 (M++H, 100%).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>C(Cl)(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([N:11]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH:9]=[N:10]2)=[O:27])[CH:22]=1
Reactant: C1=NNC(c2ccccc2)C1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1cccnc1)N1N=CCC1c1ccccc1
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
A mixture of 5-phenyl-2-pyrazoline (2.9 g) and triethylamine (4 g) was added dropwise with ice cooling to a suspension of nicotinoyl chloride hydrochloride (4 g) in 20 ml chloroform, the resulting mixture was stirred for 15 minutes, washed with water and concentrated, and the concentrate was purified by silica gel chromatography (chloroform/methanol=100/1), giving 4.3 g (yield: 86%) of pure product. M.p. 100°-102° C.; NMR (CDCl3): 2.9-3.8 (2H, m), 5.61 (1H, dd, J=5, 12 Hz), 7.03 (1H, t, J=2 Hz), 7.31 (5H, s), 7.28 (1H, m), 8.15 (1H, dt, J=8, 2 Hz), 8.68 (1H, dd, J=2, 6 Hz), 9.13(1H, d, J=2 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([C:12](OC)=[O:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(F)c2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc2c(CO)ccc(F)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of methyl 7-fluoro-2-methyl-2H-indazole-4-carboxylate (2.10 g, 10.1 mmol) in tetrahydrofuran (101 mL) was slowly added a solution (1 M, 30.3 mL, 30.3 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (1.80 g, yield 99%).
Reaction SMILES: FC1C(F)=C(C)C=CC=1CBr.O[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:17]1(=[O:18])[NH:13][C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cc1ccc(CBr)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 180 %

Procedure:
To a stirred solution of 2,3-difluoro-4-methylbenzyl bromide (Matrix, 10.47 g) and N-hydroxyphthalimide (7.73 g) in DMF (100 ml) was added drop-wise triethylamine (Et3N) (7.3 ml) (DBU may be used as an alternative to Et3N). The red reaction mixture was stirred at room temperature for 2 hours. On addition of 1 M HClaq. a white precipitate formed, that was isolated by filtration and washed with water and dried in vacuo affording a phthalimide intermediate (12.55 g, white shiny material). This compound (6.07 g) was dissolved in dichloromethane and methyl-hydrazine (1.16 ml) was added drop-wise. The reaction mixture was stirred at room temperature for 30 min. and the solid material was removed by filtration. The filtrate was evaporated under reduced pressure and purified by chromatography on silica gel (EtOAc/petroleum ether as eluent) and gave the title amine as a clear colourless oil (3.34 g). Alternatively the phthalimide intermediate can be treated with hydrazine monohydrate (1.0 eq.) in refluxing ethanol for 2-3 hours and the title compound obtained as the hydrochloride salt by treatment with 4M HCl in dioxane as described above for preparation 14. HCl salt: 13C-NMR (DMSO-d6) δ 150.0, 146.8, 128.4, 126.2, 126.1, 120.3, 68.9, 13.9. Free amine: 13C-NMR (CDCl3) δ149.2, 149.3, 127.0, 125.4, 124.5, 124.0, 70.9, 14.3
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[NH:14][C:15](=[O:17])[CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12]3[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][C:13]=3[NH:14][C:15](=[O:17])[CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC2CN(Cc3ccccc3)CCN2c2ccccc2N1
Solvent: CC(=O)O
Product: O=C1CC2CN(Cc3ccccc3)CCN2c2ccc(Br)cc2N1
Reaction time: 16 h

Procedure:
To a solution of Example 112A (1.30 g, 4.23 mmol) in acetic acid (20 mL) was added N-bromosuccinimide (0.828, 4.65 mmol). The reaction stirred for 16 hours. The reaction solution was concentrated, then partitioned between NaOH (1M) and dichloromethane. The dichloromethane layer was separated and concentrated onto silica gel. Purification via flash chromatography (30-100% ethyl acetate/hexanes) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.22-7.38 (m, 6H) 7.07 (d, J=2.37 Hz, 1H), 7.01 (d, J=8.81 Hz, 1H), 3.50-3.58 (m, 2H), 3.24-3.30 (m, 1H), 3.05-3.17 (m, 1H), 2.91-3.01 (m, 1H), 2.71-2.86 (m, 2H), 2.52-2.61 (m, 1H), 2.05-2.25 (m, 2H), 1.90 (d, J=13.22 Hz, 1H); MS (APCI+) m/z 386, 388 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]([CH3:17])[CH:15]=O>>[CH3:13][N:14]([CH3:17])/[CH:15]=[CH:1]/[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN(C)C=O
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Product: CN(C)/C=C/c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 66 %

Procedure:
The procedure was adapted from that reported J. Org. Chem. 1978, 43, 2536. Dimethylfomamide-dimethyl acetal (4 mL, 30.05 mmol) was added to a warmed) (80° suspension of 6-methyl-5-nitropyrimidine-2,4(1H,3H)-dione (3 g, 17.54 mmol) in dimethylformamide (10 ml). The resultant mixture was heated to 140° for 30 min then allowed to cool to room temperature. The solid was collected by filtration and washed with ethyl acetate then dried in vacuo to afford 6-[(e)-2-(dimethylamino)vinyl]-5-nitropyrimidine-2,4(1H,3H)-dione (2.62 g, 66%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([N+:19]([O-])=O)=[C:17]([OH:22])[C:16]([Br:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25].O>C(O)(=O)C.[Fe]>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:22])[C:16]([Br:23])=[CH:15][C:14]=2[F:24])[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c(O)c2[N+](=O)[O-])c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c(O)c2N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A stirred solution of 16.0 grams (0.037 mole) of 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione and 10 mL of water in 120 mL of glacial acetic acid was heated to 50° C., and 16.0 grams (excess) of iron dust was slowly added. The reaction mixture was then cooled to ambient temperature where it stirred for one hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was partitioned in a mixture of 150 mL portions each of water and ethyl acetate. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 12.0 grams of title compound; mp 98-100° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9].[Cl:26][C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([CH:33]=O)=[N:31][CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([CH2:33][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[CH2:2][OH:1])[CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[N:31][CH:32]=1
Reactant: Cc1cc(Cl)cnc1C=O
Reactant: CC(=O)NCc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncc(Cl)cc2C)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure B: Reaction of N-{3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzyl}-acetamide in CH2Cl2 with 5-chloro-3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave N-(4-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-acetamide as a white foam. 1H NMR (CDCl3) δ 1.58 (m, 1H), 2.03 (s, 3H), 2.04 (m, 1H), 2.18 (m, 1H), 2.24 (s, 3H), 2.65 (m, 1H), 2.79 (m, 1H), 3.69 (dd, 2H, J=12.0, 3.0 Hz), 3.79 (d, 1H, J=12.0 Hz), 3.89 (t, 1H, J=9.0 Hz), 4.12 (d, 1H, J=12.0 Hz), 4.21 (m, 1H), 4.39 (d, 2H, J=6.0 Hz), 4.41 (m, 1H), 5.67 (br s, 1H), 7.01 (dd, 1H, J=7.5, 3.0 Hz), 7.14 (d, 1H, J=6.0), 7.24-7.30 (m, 3H), 7.39 (s, 1H), 8.28 (s, 1H), 8.36 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.2, 20.8, 21.7, 23.3, 29.3, 43.4, 53.0, 54.0, 54.3, 57.7, 62.6, 65.9, 121.7, 127.1, 130.6, 131.1, 131.3, 134.6, 135.4, 136.1, 136.7, 137.6, 138.1, 142.4, 144.5, 146.6, 154.6, 156.7, 169.8. HPLC: 97%. ES-MS m/z 479 [M+H]+, 501 [M+Na]+. Anal. Calcd. for C27H31N4O2Cl 0.5 CH2Cl2: C, 62.69; H, 6.24; N, 10.63; Cl, 13.46. Found: C, 62.52; H, 6.18; N, 10.47; Cl, 13.59.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(F)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.8 %

Procedure:
To a solution of 43 mg (0.22 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 70 mg of TBTU (0.22 mmol) in 3 ml DMF, were added 0.19 ml (1.1 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 81 mg (0.22 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 30 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 63 mg (55%) of a light yellow foam. MS (ISP) 479.4 (M+H)+.
Reaction SMILES: I(O)(=O)(=O)=[O:2].C(OC([N:13]1[C@@H:17]([CH2:18][OH:19])[CH2:16][C@@H:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[C:14]1=[O:34])=O)(C)(C)C>C(#N)C.C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6].I(O)(=O)(=O)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C@H:15]2[C:14](=[O:34])[NH:13][C@@H:17]([C:18]([OH:2])=[O:19])[CH2:16]2)=[CH:25][CH:24]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]1CO
Reactant: [O-][I+3]([O-])([O-])O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1N[C@@H](C(=O)O)C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing 6.0 g of periodic acid and chromium trioxide (13 mg) in wet acetonitrile (60 mL; 0.75 volume % water) was prepared. A portion of this solution (15 mL) was added dropwise to a solution of (3S,5R)-3-(4-benzyloxyphenyl)-5-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.02 g, 2.57 mmol) in wet acetonitrile (15 mL; 0.75 volume % water) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. At this time, more of the periodic acid/chromium trioxide solution (5 mL) was added. Stirring at 0° C. was continued for an additional 1 hour. After quenching with a solution of dibasic sodium phosphate (720 mg) in water (12 mL), the mixture was extracted twice with diethyl ether. The combined organic extracts were washed with aqueous sodium bisulfite solution (440 mg in 10 mL water) and brine. After drying over MgSO4, the solvent was evaporated to provide a yellow solid that was taken up in methylene chloride (100 mL) and cooled in an ice bath. Hydrogen chloride gas was bubbled through the cold solution for 2 minutes and the resulting mixture was stirred at 0° C. for 1 hour. The solvent and HCl were evaporated to afford a solid from which the title compound, 226 mg (28%) was isolated by trituration with a mixture of methylene chloride, diethyl ether and ethyl acetate. The trituration filtrate was dissolved in aqueous saturated NaHCO3 solution and washed twice with diethyl ether. After careful acidification with aqueous 6M HCl solution, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to provide more of the title compound, 123 mg (15%).