Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.C(OC([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=O)(C)(C)C.CN1CCOCC1>C1COCC1>[NH2:31][C@H:32]([C:34]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)=[O:35])[CH3:33]
Reactant: Nc1ccc2c(c1)C(=Cc1ccc(O)c3ncccc13)C(=O)N2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](N)C(=O)Nc1ccc2c(c1)C(=Cc1ccc(O)c3ncccc13)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-amino-3-(8-hydroxyquinol-5-ylmethylen)-2-oxindole (497 mg, 1.64 mmol) and of t-butoxycarbonyl-L-alanine (360 mg, 1.9 mmol in 80 ml of THF were added 950 mg (1.82 mmol) of benzotriazol-1-yloxytripyrrolidinophosphoniun hexafluorophosphate and 0.2 ml (1.87 mmol) of N-methylmorpholine. The reaction was maintained at room temperature for 4 h. After evaporation of the solvent the residue was purified by flash chromatography with cyclohexane/ethyl acetate 3:7. The evaporated eluant was solubilized in dichloromethane, 10 ml of trifluoroacetic acid was added and the mixture stirred at room temperature for 1 h. After the usual workup pure title compound was obtained in 80% yield (491 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][CH2:8][CH2:9]Cl>>[CH3:6][O:7][CH2:8][CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COCCCl
Product: COCCN1CCCC1
Reaction time: 48 h

Procedure:
In an autoclave of 100 mL, pyrrolidine (40.0 g, 563 mmol) was made reacted with chloroethyl methyl ether (26.0 g, 275 mmol) at 125 deg C. for 48 hours. Solid salt that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 25 cm. Then 1H-NMR measurement of obtained amine is performed, and it was confirmed that chemical shifts, δ (ppm), are 3.46-3.43 (t, 2H), 3.30(s, 3H), 2.62-2.59(t, 2H), 2.49-2.46(m, 4H), and 1.73-1.70 (m, 4H), and that N-2-methoxyethylpyrrolidine was synthesized.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][CH3:34])[CH2:19][CH2:18]1.C(N(CC)CC)C.[C:43](Cl)(Cl)=[S:44]>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:33]([CH3:34])[C:43]2=[S:44])[CH2:19][CH2:18]1
Reactant: S=C(Cl)Cl
Reactant: CNc1ccccc1C(=O)NCCN1CCC(Cc2nc3cccnc3n2Cc2ccco2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=S)n(CCN2CCC(Cc3nc4cccnc4n3Cc3ccco3)CC2)c(=O)c2ccccc21
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a stirred mixture of 8 parts of N-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2-(methylamino)benzamide, 13 parts of N,N-diethylethanamine and 130 parts of dichloromethane was added dropwise a solution of 2.3 parts of carbonothioic dichloride in dichloromethane. Upon completion, stirring was continued for 2 hours. The reaction mixture was evaporated. The residue was crystallized from a mixture of methanol and ethanol. The product was filtered off and boiled in methanol. The product was filtered off and dried, yielding 3 parts (34.3%) of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-1-methyl-2-thioxo-4(1H)-quinazolinone; mp. 169.2° C. (486).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:16][CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:19].O>ClC1C=CC=CC=1>[CH2:1]([O:8][N:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:19])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC(=O)OC)=NOCc1ccccc1
Reactant: O=[Se]=O
Solvent: O
Solvent: Clc1ccccc1
Product: CCC(=NOCc1ccccc1)C(=O)C(=O)OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of 47.06 g (0.2 mol) of methyl 3-benzyloxyiminovalerate in 150 ml of chlorbenzene, 24.41 g (0.22 mol) of selenium dioxide was added and the mixture was stirred for 8 hours at 120° C. After adding 200 ml of water and filtering through Celite, the filtrate was extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 31.15 g (yield 62%) of methyl 3-benzyloxyimino-2-oxovalerate as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:31][C:32]1[C:33](=[O:48])[N:34]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[F:47])[C:35](=[O:39])[NH:36][C:37]=1[NH2:38]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[NH:31][C:32]2[C:33](=[O:48])[N:34]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:35](=[O:39])[NH:36][C:37]=2[NH2:38])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
A solution of (4-tert-butoxycarbonylamino-phenyl)-acetic acid in N,N-dimethylformamide under argon at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction was stirred at 25° C. for 5 min. At this time, the reaction was treated with 5,6-diamino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione and 4-dimethylarninopyridine. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (75 mL) and then acidified to pH=5 with a 1.0N aqueous hydrochloric acid solution. The resulting solid was collected by filtration, rinsed well with water and cold ether, and dried in vacuo to afford (4-{[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester (4.10 g, 91%) as a yellow solid; LRMS for C28H32FN5O5 (M+H)+ at m/z=538.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH3:9][O:10][C:11]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:12]=1[C:13](OC)=[O:14].Cl>C1COCC1>[CH3:9][O:10][C:11]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:12]=1[C:13](=[O:14])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1C(=O)CC#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of acetonitrile (3.24 mL; 61.7 mmol) in dry THF (31 mL) at −78° C. under nitrogen atmosphere was added n-butyllithium 2.5M (15.4 mL; 38.5 mmol) and the reaction mixture was stirred at −78° C. for 30 minutes. Then, a solution of methyl 2-methoxy-4-methylbenzoate (2.78 g; 15.4 mmol) in dry THF (18 mL) was added dropwise and the stirring was continued for 1.5 hour. The reaction mixture was hydrolyzed by adding HCl (1N) and the aqueous layer was extracted several times with ethyl acetate. The organics were combined, dried over magnesium sulphatesulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate (5 to 80%) in heptane to furnish 2.5 g of the expected 3-(2-methoxy-4-methylphenyl)-3-oxopropanenitrile (86%) as a bright yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17][C:18]([CH3:29])=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>CN(C=O)C>[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH:19]=[C:18]([CH3:29])[CH2:17][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: CC(=Cc1ccc(C(C)C)cc1)CBr
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccc(C(C)C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (3.00 g, 16.7 mmol) in DMF (30 mL) was added sodium hydride (a 60% liquid paraffin dispersion, 0.74 g, 18.4 mmol) under nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 1-(3-bromo-2-methyl-1-propenyl)-4-isopropylbenzene synthesized in Reference Example 108 (4.66 g, 18.4 mmol) and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was twice extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain 3.70 g (yield 63%) of the title compound. Melting point: 153-155° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(OCCO)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH:20]([OH:22])[CH2:19][O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:1]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1ccc(OCC(O)COc2ccccc2)cc1O
Reaction time: 48 h

Procedure:
A solution of resacetophenone (15.2 g), phenylglycidyl ether (15.0 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution) in 2-ethoxyethanol (75 ml) was heated under reflux for 2 days. Removal of solvent under reduced pressure yielded a dark, viscous oil, which was allowed to stand for 48 hours, by which time it had crystallized to a solid mass. This was triturated with a mixture of ether and light petroleum (b.p. 40°-60°.), filtered, washed with a little more ether-petroleum and dried. Crystallization from methanol gave 1-(4-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-phenoxypropane as a greyish-white solid, 9.0 g, m.p. 63°-65°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH3:41])[CH:34]=[CH:35][C:36]=1[C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl>[C:27]([O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:41][Br:1])(=[O:29])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)ccc1C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1C(C)(C)C

Procedure:
16.4 g of N-bromosuccinimide, 1 g of α,α'-azoisobutyronitrile and 1 g of dibenzoyl peroxide are added in succession to a solution, stirred at 70° C. of 19 g of 3-acetoxy-4-tert-butyltoluene in 900 ml of CCl4. The reaction mixture is stirred under reflux for 31/2 hours under UV irradiation and is filtered, and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of FC (900 g of silica gel, hexane/ethyl acetate=95:5): Rf (hexane/ethyl acetate=95:5)=0.40.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]=O)=[CH:29][CH:30]=3)[N:25](COCC[Si](C)(C)C)[N:24]=2)=[CH:17][CH:16]=1>>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:32]\[C:28]1[CH:27]=[C:26]3[C:31]([C:23](/[CH:22]=[CH:21]/[C:18]4[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=4)=[N:24][NH:25]3)=[CH:30][CH:29]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1cccc2c1NC(=O)C2
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Product: CC(=O)Nc1cccc2c1NC(=O)/C2=C/c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 94.9 %

Procedure:
According to the method of A57B, N-(2-oxoindolin-7-yl)acetamide (30 mg, 0.16 mmol) was reacted with (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (60 mg, 0.16 mmol) to give the title compound as an orange solid (64 mg, 72%). MS ESI 552.3 [M+H]+, calcd for [C31H33N5O3Si+H]+ 552.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].C([C:20]1[CH:25]=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:23]=[CH:22][N:21]=1)=C>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH:26]([C:24]3[CH:23]=[CH:22][N:21]=[CH:20][CH:25]=3)[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cc(C(=C)C)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was dissolved in NMP (3 mL) and KOH (280 mg, 5 mmol) was added with vinyl 4-(prop-1-en-2-yl)pyridine (178 mg, 1.5 mmol). The reaction was stirred at RT for 14 h. After completion, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, concentrated and the residue purified by HPLC. 1HNMR (CD3OD, Oxalate salt) d (ppm): 8.4 (d, 2H), 7.25-7.15 (m, 4H), 7.05 (d, 1H), 4.4-4.2 (m, 3H), 3.80-3.79 (m, 2H), 3.50-3.40 (m, 2H), 3.15 (m, 1H), 3.05 (s, 3H) 2.70 (m, 1H), 2.40 (s, 3H), 1.40 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@@H:4]([OH:23])[C@H:3]([CH2:2][NH:1][CH2:35][C:32]3[CH:33]=[CH:34][C:28]4[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=4[N:31]=3)[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@@H](CN)[C@H](O)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 62 %

Procedure:
To a stirred solution of (±)-trans-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.62 g, 1.94 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.38 g, 1.94 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.61 g, 2.91 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.60 g, 62%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 4.11 (s, 3H), 4.05 (m, 4H), 3.52 (m, 4H), 3.42 (s, 2H), 3.19 (m, 2H), 2.98 (m, 2H), 2.70 (m, 2H). LC-MS (ES) m/e 499 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][CH2:38][CH:37]1[CH2:46][NH2:47]>CN(C=O)C>[O:36]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][CH2:38][CH:37]1[CH2:46][NH:47][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCC(CNCCCc1c[nH]c3ccccc13)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
3-Indolepropionic acid (1.1 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.2 g, 6.0 mmole) in 50 ml of DMF, and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as an oily solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[C:8]([O:12][C:13](=[O:39])[NH:14][C:15]([CH3:38])([CH3:37])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[CH:20][C:19]=1[NH2:36])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13](=[O:39])[NH:14][C:15]([CH3:38])([CH3:37])[CH2:16][N:17]1[C:18]2[C:27]3[CH:26]=[C:25]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:36]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(CNc1c(N)cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
Ethoxyacetyl chloride (3.5 mL, 32.0 mmol) was added to a solution of tert-butyl[2-(3-amino-6-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (12.71 g, 29.1 mmol) and triethylamine (8.1 mL, 58.2 mmol) in approximately 250 mL of anhydrous dichloromethane. After stirring for 2 hours, the volatiles were removed under reduced pressure and the resulting brown residue was dissolved in ethanol, followed by the addition of 8.1 mL of triethylamine. The reaction was heated at reflux for 2.5 days and then cooled to ambient temperature. The solvent was removed under reduced pressure and dichloromethane was added. The solution was sequentially washed with aqueous sodium bicarbonate (2×) followed by brine; dried over sodium sulfate; filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 0-15% CMA in chloroform to provide 8.4 g of tert-butyl[2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate as an orange foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([F:18])[CH:11]=2)=[N:21][CH:22]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccc(Br)cn2)ccc1OCc1ccccc1
Temperature: 90 °C
Yield: 76.7 %

Procedure:
(4-Benzyloxy-3-fluorophenyl)boronic acid (1.06 g, 4.22 mmol) was added to a suspension of 2,5-dibromopyridine (1.0 g, 4.22 mmol) in toluene (8 mL), followed by addition of 2M Na2CO3 (6 mL) and Pd(PPh3)4 (0.15 g, 0.13 mmol) and EtOH (2 mL). The reaction mixture was degassed with N2 and heated at 90° C. overnight. The mixture was cooled to ambient temperature, water was added, and the mixture was extracted with EtOAc. The combined organic extract was washed with brine, dried over Na2SO4, filtered through a pad of silica gel, and the filtrate was concentrated to give a solid, which was recrystallized from MeOH to give 1.16 g (77%) of 5-bromo-2-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}pyridine as a faint yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.69 (d, 1H, J=2.2 Hz), 7.85 (dd, 1H, Ja=8.4 Hz, Jb=2.1 Hz), 7.77 (dd, 1H, Ja=12.4 Hz, Jb=2.1 Hz), 7.67 (d, 1H, J=8.6 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.50-7.30 (m, 5H), 7.07 (t, 1H, J=8.4 Hz), 5.20 (s, 2H); LRMS (ESI), m/z 358/360 (M+H).
Reaction SMILES: Cl.Cl.Cl.[N:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][N:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41](Cl)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41]([N:7]1[CH2:6][CH2:5][N:4]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][N:11]=2)[CH2:9][CH2:8]1)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: c1cncc(-c2cnc(N3CCNCC3)nc2)c1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 81.6 %

Procedure:
Prepared according to the method for the preparation of4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 2-piperazin-1-yl-5-pyridin-3-ylpyrimidine, trihydrochloride (0.292 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.343 g), to yield the title compound as a yellow solid (0.393 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:20])[CH2:7]1
Reactant: Cc1ccc(CN=C=O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1ccc(CNC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1

Procedure:
Example 3 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-(isocyanatomethyl)-4-methylbenzene (19.1 μl) to give the title compound (0.0318 g). LC-MS (System A): Rt 2.33 mins, Mass Spectrum m/z 422 [MH+].