Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[N:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](=[O:33])[NH:11][CH2:10][CH2:9][C:8]3[C:3]([O:2][CH3:1])=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][CH:7]=3)=[CH:30][CH:29]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: COc1nc(C(F)(F)F)ccc1CCN
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)nc4OC)cc3)c(Cl)cc21
Reaction time: 14 h
Yield: 71.6 %

Procedure:
2-(2-Methoxy-6-(trifluoromethyl)pyridin-3-yl)ethanamine (140 mg, 0.637 mmol) in dichloromethane (1 ml) was treated sequentially with 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 240 mg, 0.637 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (147 mg, 0.764 mmol), and 4-(dimethylamino)pyridine (7.78 mg, 0.0637 mmol) at ambient temperature. After 14 hours, the reaction was applied directly to silica gel. Elution with ethyl acetate (50-80%) provided the desired compound (264 mg, 0.456 mmol, 71.6% yield) as a white solid.
Reaction SMILES: [N:1]1([CH2:9][C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:22]([CH3:23])[C@H:21]4[N:18]([C:19](=[O:27])[C@@H:20]4[C@H:24]([OH:26])[CH3:25])[C:17]=3[C:28]([O:30]CC3C=CC([N+]([O-])=O)=CC=3)=[O:29])[CH2:12][N:11]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.P(=O)(O)(O)O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[N:1]1([CH2:9][C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:22]([CH3:23])[C@H:21]4[N:18]([C:19](=[O:27])[C@@H:20]4[C@H:24]([OH:26])[CH3:25])[C:17]=3[C:28]([OH:30])=[O:29])[CH2:12][NH:11]2)[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CN4CCn5nccc54)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CN4CCn5nccc54)C3)[C@H](C)[C@H]12
Yield: 71.5 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.70 g), 20% palladium hydroxide on carbon (0.4 g), 01 M phosphoric acid buffer (pH=6.0, 35 ml) and tetrahydrofuran (35 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to remove the organic solvent. The aqueous layer was washed twice with ethyl acetate (30 ml) and evaporated in vacuo to remove the organic solvent. The residue was chromatographed on a nonionic adsorption resin "Diaion HP-20" (20 ml) eluting in turn with water (60 ml) and 5% aqueous acetone [120 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidin-4-yl ]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (0.29 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc(CCC(=O)O)cc1
Reaction time: 2 h

Procedure:
A solution containing 18 g of 4-ethylcinnamic acid dissolved in 50 mL of acetic acid was placed in a Parr Shaker bomb flask, 1.0 g of 5% palladium on carbon catalyst was added, and the flask was pressured to 50 psig (pounds per square inch gauge) (4460 kiloPascals) for 2 hours. The catalyst was then removed by filtration and the solution was concentrated by evaporation under reduced pressure. Water was added to the residue and the solid present was collected by filtration and dried under reduced pressure to obtain 3-(4-ethylphenyl)propanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH:17]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[CH:25]=[CH:24]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][N:37]3[CH2:36][CH2:35][N:34]([S:31]([C:26]4[CH:25]=[CH:24][C:23]5[C:28](=[CH:29][CH:30]=[C:21]([Cl:20])[CH:22]=5)[CH:27]=4)(=[O:33])=[O:32])[CH2:39][CH2:38]3)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1

Procedure:
In a similar manner to Referential Example 47 except for the use of 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][C:4]=1[NH2:5].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:23]=1[N:30]1[C:34](=[O:35])[CH2:33][C:32](OCC)=[N:31]1.ClC1C=C(Cl)C(OCCCCCCCCCCCCCCCC)=CC=1N.FC1C=CC([N+]([O-])=O)=CC=1.C(Br)CCCCCCCCCCCCCCC>>[Cl:29][C:24]1[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[C:23]=1[N:30]1[C:34](=[O:35])[CH2:33][C:32]([NH:5][C:4]2[CH:6]=[C:7]([O:11][C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:8]([Cl:10])=[CH:9][C:3]=2[Cl:2])=[N:31]1
Reactant: CCOC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)cc1Cl
Agent: CCCCCCCCCCCCCCCCBr
Agent: CCCCCCCCCCCCCCCCOc1cc(N)c(Cl)cc1Cl
Agent: Cl
Product: O=C1CC(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Yield: 51.6 %

Procedure:
Using 11.6 g of 2,4-dichloro-5-(4-nitrophenoxy)-aniline hydrochloride and 13.1 g of 1-(2,4,6-trichlorophenyl)-3-ethoxy-2-pyrazolin-5-one, which were prepared in a manner similar to Steps (1) and (2) of Synthesis Example 1 except that 21.2 g of 4-fluoronitrobenzene was used in lieu of hexadecyl bromide in Step (1) of Synthesis Example 1, procedures similar to Step (3) of Synthesis Example 1 were carried out. In this case, 10.0 g of the desired product was obtained without recrystallization. The melting point thereof was 305 to 306° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[O:8][CH2:7][C:6]1=[O:18].[BH4-].[Na+]>O1CCCC1.CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[OH:18]
Reactant: COc1ccc2c(c1)SC(CCCCl)C(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)SC(CCCCl)C(O)CO2
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-one (0.8 g) in tetrahydrofuran (2 ml) and methanol (10 ml) is added sodium borohydride (0.1 g) under ice-cooling. The reaction mixture is stirred for another one hour and evaporated in vacuo. The residue is mixed with ethyl acetate and water. The orgonic layer is separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is submited to column chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to give 4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol (0.68 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:2]1
Reactant: OC1(c2ccoc2)CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CC(c2ccoc2)c2ccccc21
Yield: 61.7 %

Procedure:
To a mixture of 5 g (0.024 mol) of 1-(3-furyl)-indan-1-ol in 500 mL of toluene was added 50 mg of p-toluenesulfonic acid monohydrate and the solvent was distilled in vacuo (40 mm) until a residue was obtained. The residue was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 2.7 g (61.3%) of 1-(3-furyl)-indene as a clear oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#N.S(=O)(=O)(O)[OH:27]>C1C=CC=CC=1.C(OCC)C>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:27]
Reactant: N#CCCCCCCOC1CCCCO1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CCCCCCCOC1CCCCO1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (19.4 g.) in dry benzene (50 ml.) was added dropwise at 10° C. to a stirred solution of 7-(2-tetrahydropyranyloxy)heptanenitrile (20.6 g.) in dry diethyl ether (200 ml.). The solution was stirred at 10° C. for 30 minutes and was then added to 2N aqueous sulphuric acid (300 ml.) at 0° C. The mixture was heated at 30° C. for 30 minutes, and then saturated with sodium chloride and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with aqueous sodium bicarbonate, and then aqueous sodium chloride, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanal (12.7 g.), b.p. 78°-106° C./0.1 mm.Hg, nD25 1.456.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][CH:4]=[C:3]([Cl:8])[CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:13](Cl)(=[O:15])[CH3:14]>O>[CH3:14][C:13]([C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[Cl:8])=[O:15]
Reactant: Clc1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Reaction time: 7 h

Procedure:
147 g (1.0 mol) of p-dichlorobenzene are completely melted at 60° C. in an apparatus having an attached dropping funnel, stirrer and reflux condenser. 120 g (0.9 mol) of anhydrous AlCl3 are added to the melt. 39.3 g (0.5 mol) of acetyl chloride are then added dropwise to the readily stirrable suspension at 60° C. in the course of about 1 hour, a clear solution slowly resulting. After heating to 110° C., the mixture is stirred at this temperature for 7 hours. After cooling to room temperature, the brown reaction mass is hydrolysed by cautious decantation onto a mixture of 200 ml of water and 200 g of ice. The temperature of the mixture is kept between 30 and 40° C. during the hydrolysis by external cooling. After separation of the phases, the lower, organic phase is washed with 400 ml of water and, after fresh phase separation, subjected to fractional distillation. The aqueous phases are discarded.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:43]1([C:49]2[O:53][N:52]=[C:51]([NH2:54])[CH:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN1CCOCC1>CN1C(=O)CCC1>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:54][C:51]4[CH:50]=[C:49]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:53][N:52]=4)=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: Nc1cc(-c2ccccc2)on1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: O=C(Nc1cc(-c2ccccc2)on1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.2 %

Procedure:
A 2-5 mL microwave reactor vial is charged with a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 25 mg, 0.10 mmol) in NMP (2 mL). HATU (47 mg, 0.12 mmol) is added and the mixture is stirred at room temperature for 30 min. 5-phenyl-3-aminoisoxazole (66 mg, 0.41 mmol) and N-methylmorpholine (41 mg, 0.41 mmol) are added and the vial is sealed with a Teflon lined septa cap and is irradiated in a microwave reactor at 100° C. for 30 min then at 150° C. for 90 min. The mixture is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/water with 0.1% TFA to obtain the title compound (2 mg, 5%). LCMS: 387.20 (M+H+). (System V1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18](OCC)=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:16](=[CH:15][CH:14]=[C:13]([F:12])[CH:23]=2)[NH:24][C:10]1=[O:11]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(F)ccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
A solution of 2,4-dichlorophenyl isocyanate (47.0 g, 0.25 mol) in xylene (130 ml) is metered at room temperature into a solution of ethyl 5-fluoroanthranilate (45.2 g, 0.25 mol) in xylene (210 ml). After addition is complete, the mixture is stirred at 90° C. for 2.5 hours. 4.50 ml of a 30% strength solution of methanolic sodium methoxide (0.025 mol) are metered in and the mixture is stirred at 90° C. for a further 2 hours, ethanol and methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×30 ml of xylene. The xylene-moist precipitate is treated with dilute hydrochloric acid and the residual xylene is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 73.4 g of 3-(2,4 dichlorophenyl)-6-fluoro-2,4(1H,3H)-quinazolinedione (yield: 90.3% of theory) of melting point 313° to 314° C. are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:37]1[C:38]2[C:45]([CH3:46])=[CH:44][NH:43][C:39]=2[N:40]=[CH:41][N:42]=1>C(O)(C)C>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:18][N:17]([C:37]3[C:38]4[C:45]([CH3:46])=[CH:44][NH:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 110 °C

Procedure:
To a solution of 3-(4-(2-methoxyethoxy)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D, and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol) in isopropanol (1.0 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (55 mg, 0.322 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 h, during which time the mixture became homogenous. The mixture was concentrated under vacuum and purified by prep HPLC (30×100 mm C18 column, 5-100% acetonitrile:water (10 mM NH4OAc), 15 min, 45 mL/min) to afford the title compound (17.4 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl (2-fluoro-5-nitrophenyl)carbamate (3.54 g, 13.8 mmol) in MeOH (100 mL) was added catalyst 10% Pd/C (0.15 g). The reaction was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellowish solid (2.02 g, 65%).
Reaction SMILES: [F:1][C:2]1[C:12]([CH2:13][O:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:12]([CH2:13][O:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[N:19][CH:20]=2)=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][OH:5]
Reactant: CCOC(=O)c1cccc(COc2cnc(N3CCOCC3)nc2)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cccc(COc2cnc(N3CCOCC3)nc2)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (375 mg) was mixed with toluene (5 ml), followed by cooling to 0° C. A 1.01 M diisobutylaluminum hydride/toluene solution (3 ml) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. The reaction mixture was subjected to liquid separation by the addition of a 1 M aqueous NaOH solution and toluene. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)phenyl]methanol (282 mg).
Reaction SMILES: [H-].[H-].COCCO[Al+]OCCOC.[Na+].[CH2:15]([N:22]([CH2:30][CH:31]([C:37](OCC)=[O:38])[C:32](OCC)=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCCCCC>C1(C)C=CC=CC=1>[CH2:15]([N:22]([CH2:30][CH:31]([CH2:37][OH:38])[CH2:32][OH:33])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)C(=O)OCC
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: OCC(CO)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 35 °C
Yield: 69.8 %

Procedure:
A flask is charged with toluene (160 mL) and sodium bis(2-methoxyethoxy)aluminum dihydride (Red-Al, 137.9 g, 443.4 mmol, 65 wt. % in toluene). The solution is heated to 35° C. and treated with a solution of 2 (54.6 g, 369.5 mmol) in toluene (110 mL) at a rate sufficient to maintain the reaction temperature between 35-42° C. The reaction is stirred while cooling gradually at about 30° C. for 2 hours. The reaction is further cooled to 5° C. and quenched with ethyl acetate (10.3 mL) followed by 1.85N aqueous NaOH solution (176 mL), and the layers are separated. The organic phase is treated with a solution of sodium potassium tartrate (13.65 g) in water (112 mL), and the mixture is heated at 50° C. for about 15 minutes. After cooling at about 25° C., the layers are separated. The organic phase is washed with water (180 mL), and then concentrated by distillation under vacuum at about 50-55° C. to an oil. Toluene (30 mL) is added and the resultant solution is seeded with crystals of 3 (see below) and stirred at about 25° C. for 1 hour. At this point a thick slurry is obtained. Heptane (250 mL) is added dropwise over 30 minutes, stirred an additional 2 hours, and filtered. The solid is washed with heptane and dried under vacuum to provide 3 as a white solid. Yield: 30.4 g, 69.8% yield: Purity: 96.8 wt. %.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:21])[C:12]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=3[F:20])[C:6]=2[CH:5]=[CH:4][N:3]1[CH2:22][C:23]1[N:24]=[C:25]2[CH:30]=[C:29]([C:31]([OH:33])=O)[CH:28]=[CH:27][N:26]2[CH:34]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:49][NH:50][CH3:51]>CN(C=O)C.CC#N>[CH3:49][N:50]([CH3:51])[C:31]([C:29]1[CH:28]=[CH:27][N:26]2[CH:34]=[C:23]([CH2:22][N:3]3[CH:4]=[CH:5][C:6]4[C:10]([C:11](=[O:21])[C:12]5[C:13]([F:20])=[CH:14][C:15]([F:19])=[CH:16][C:17]=5[F:18])=[CH:9][NH:8][C:7]=4[C:2]3=[O:1])[N:24]=[C:25]2[CH:30]=1)=[O:33]
Reactant: O=C(O)c1ccn2cc(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccn2cc(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To the product obtained in Example 23 (4.7 mg, 0.010 mmol) in DMF were added EDC (2.51 mg, 0.013 mmol), HOBt (2.06 mg, 0.013 mmol) and dimethylamine (3.83 μL, 0.030 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with 3:2 MeCN:H2O (2 mL) and purified by reverse phase HPLC (C-18 column) to give the title compound (3.1 mg). LC/MS: m/z 494(M+H). 1H-NMR (500 MHz, d6-DMSO): δ 2.92 (s, 3H), 2.99 (s, 3H), 5.43 (s, 2H), 6.99 (d, 1H), 7.15 (d, 1H), 7.33 (t, 2H), 7.58 (d, 1H), 7.73 (s, 1H), 7.89 (d, 1H), 8.03 (s, 1H), 8.66 (d, 1H), 13.1 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2.[CH3:13]N(C)CCN(C)C.[Li+].CCC[CH2-].IC.Cl.[Cl-].[Na+]>C(OCC)(=O)C.CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]([CH3:13])[C:6](=[O:12])[NH:7]2
Reactant: CN(C)CCN(C)C
Reactant: COc1cccc2c1CC(=O)N2
Agent: Cl
Agent: [CH2-]CCC
Agent: [Cl-]
Solvent: CO
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cccc2c1C(C)C(=O)N2
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 101.3 %

Procedure:
A mixture of tetrahydrofuran (990 mL), 4-methoxyindolin-2-one (J. Chem. Soc., 3904, 1952; Tetrahedron, 24:6093, 1968, 39.60 g, 242.7 mmol), and N,N,N′,N′-tetramethylethylenediamine (56.40 g, 485.4 mmol) is cooled to −78° C. N-butyllithium (379.2 mL, 606.7 mmol, 1.6M in hexanes) is added over 1 hour so as to maintain the reaction temperature between −70° C. and −69° C. After stirring the mixture for 50 minutes at −78° C., iodomethane (36.17 g, 254.8 mmol) is added over 50 minutes at −78° C. to −64° C. The reaction mixture is allowed to warm to −40° C. and iodomethane (48.23 g, 0.3398 mol) is added incrementally over 1 hour until the starting material is less than 3 percent by HPLC (retention 7.3 minutes; Zorbax SB-Phenyl (4.6 mm×25 cm); solvent A—trifluoroacetic acid solution (0.1%, v/v); solvent B—acetonitrile; 1.0 mL/min; 254 nm; gradient method: 0.00–2.00 minutes, 30% A, 70% B; 2.00–7.00 minutes, linear ramp from 30% A, 70% B to 80% A, 20% B; 7.00–15.00 minutes, 80% A, 20% B). Methanol (20 mL) is added to the reaction mixture over 15 minutes at −60° C. to −50° C. Aqueous hydrochloric acid (1N, 250 mL) is added allowing the temperature to rise to −4° C. The solution is transferred to a separatory funnel with ethyl acetate (500 mL), aqueous hydrochloric acid (1N, 250 mL) and a saturated sodium chloride solution (250 mL). After separating, the organic layer is extracted twice with aqueous hydrochloric acid (1N, 250 mL) and the aqueous layer is extracted with ethyl acetate (250 mL). The combined organic layers are washed with a saturated sodium chloride solution (250 mL) then dried over magnesium sulfate. After filtration, the solvents are removed by rotary evaporation to give 43.58 g (91.6%) of 4-methoxy 3-methyl-1,3-dihydro-indol-2-one as a solid, mp 128–130° C. MS (ES+) m/z 178 (M++1).