Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[S:2]([C:5]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH:20]([CH3:22])[CH3:21])[C:6]=1[C:7]([N:9](C)[CH3:10])=[O:8])(=[O:4])=[O:3].C(C1C(OC)=C(OC)C=C2C=1C(=O)NS2(=O)=O)(C)C.C1(SC[Cl:50])C=CC=CC=1.C1(SCN2C(=O)C3C(=CC(OC)=C(OC)C=3C(C)C)S2(=O)=O)C=CC=CC=1.S(Cl)(Cl)(=O)=O>C(OCC)(=O)C.CCCCCC>[Cl:50][CH2:10][N:9]1[C:7](=[O:8])[C:6]2[C:5](=[CH:15][C:14]([O:16][CH3:17])=[C:13]([O:18][CH3:19])[C:12]=2[CH:20]([CH3:22])[CH3:21])[S:2]1(=[O:4])=[O:3]
Reactant: COc1cc(S(N)(=O)=O)c(C(=O)N(C)C)c(C(C)C)c1OC
Reactant: ClCSc1ccccc1
Agent: COc1cc2c(c(C(C)C)c1OC)C(=O)N(CSc1ccccc1)S2(=O)=O
Agent: COc1cc2c(c(C(C)C)c1OC)C(=O)NS2(=O)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(=O)(Cl)Cl
Product: COc1cc2c(c(C(C)C)c1OC)C(=O)N(CCl)S2(=O)=O
Yield: 85 %

Procedure:
By the method of Example 22A 2-aminosulfonyl-4,5-dimethoxy-6-isopropyl-N,N-dimethylbenzamide (10.75 g) was prepared and cyclized to 4-isopropyl-5,6-dimethoxysaccharin (mp 186°-188° C. from ether-hexane), phenylthiomethylation of part (5 g) of which with chloromethyl phenyl sulfide (2.48 mL) gave 2-phenylthiomethyl-4-isopropyl-5,6-dimethoxysaccharin (4.07 g), reaction of which with sulfuryl chloride (three molar equivalents) gave 2-chloromethyl-4-isopropyl-5,6-dimethoxysaccharin, 85% yield, mp 117°-119° C. from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:20]1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:19][CH:20]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1c[nH]c2ccccc12
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3c[nH]c4ccccc34)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(1H-indol-3-yl)-acrylic acid. LC-MS-conditions 05b: tR=0.84 min; [M+H]+=375.31.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[C:20]([NH2:35])[CH:21]=[C:22]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:23]=2)[CH:13]=1>C1COCC1>[CH3:8][NH:9][C:10]([NH:35][C:20]1[CH:21]=[C:22]([NH:24][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=2)[CH:23]=[C:18]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:19]=1)=[O:11]
Reactant: CN=C=O
Reactant: Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccnc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccnc2)c1
Temperature: 40 °C

Procedure:
Triethylamine (44.2 μL, 0.317 mmol) followed by methyl isocyanate (18.1 mg, 0.317 mmol was added to a solution of 5-(pyridin-3-yl)-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzene-1,3-diamine (35 mg, 0.106 mmol) in THF (264 μL). The reaction mixture was heated to 40° C. for 4 hours, then cooled to room temperature and concentrated under reduced pressure. The solid was diluted with diethyl ether (5.00 mL) and was filtered to isolate 1-methyl-3-[3-(pyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]urea as a tan powder. The product was further dried under reduced pressure. MS APC calc'd for C18H16F3N6O [M+H]+ 389. found 389. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.26 (s, 1H), 6.06 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: CO[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[Cl:13].[C:15]([C:17]1[C:25]([CH3:26])=[CH:24][C:20](C(O)=O)=[CH:19][C:18]=1[CH3:27])#[N:16]>>[Cl:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([C:20]1[CH:24]=[C:25]([CH3:26])[C:17]([C:15]#[N:16])=[C:18]([CH3:27])[CH:19]=1)=[O:14]
Reactant: Cc1cc(C(=O)O)cc(C)c1C#N
Reactant: COC(=O)Cc1ccc(OC)cc1Cl
Product: COc1ccc(CC(=O)c2cc(C)c(C#N)c(C)c2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 138, steps 1 and 2, from (2-chloro-4-methoxy-phenyl)-acetic acid methyl ester and 4-cyano-3,5-dimethyl-benzoic acid (CAS [90924-01-0]). Orange solid. MS (m/e, ISP neg. ion)=312.1 [M−H+].
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][C:4]=1[CH3:12])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[OH-].[Na+].Cl>CC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([NH:11][S:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([CH3:12])[CH:5]=2)(=[O:9])=[O:10])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CCc1sc(S(N)(=O)=O)cc1C
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1sc(S(=O)(=O)NC(=O)Nc2ccc(Cl)c(Cl)c2)cc1C
Yield: 27.4 %

Procedure:
The procedure of Example 4B was followed with 5-ethyl-4-methyl-2-thiophenesulfonamide (1.5 g, 7.3 mmole), 3,4-dichlorophenyl isocyanate (1.38 g, 7.3 mmole), acetone (7 0 ml), 1H NaOH (7.3 ml), concentrated HCl to give the named product as a white solid (2.17 g, 5 2 mmole).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]2[N:9]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[C:25]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=5)=[CH:24][CH:23]=[C:22]([C:33](=[O:35])[NH2:34])[CH:21]=4)=[CH:14][C:13]=3[F:36])=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:33]([C:22]1[CH:21]=[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]3[N:9]([CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)[C:8]4[CH:43]=[CH:44][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)=[C:13]([F:36])[CH:14]=2)[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1)(=[O:35])[NH2:34]
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(C(N)=O)ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)c(F)c2)c1
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
Compound 59 (0.12 g, 0.196 mmol) was dissolved in MeOH (6 mL) and 2 M aqueous NaOH (3 mL) was added. The reaction mixture was stirred at 45° C. for 2.5 h and cooled down to 0° C. The mixture was neutralized with 5 N HCl to pH 3. After evaporation of solvent, the residue was dried under high vacuum and dissolved in DMF. After filtration, filtrate was concentrated by evaporation to a small volume and the product was separated by C18 reverse phase HPLC using buffer A (1% TFA in water) and buffer B (1% TFA acetonitrile) from 10% buffer B to 70% buffer B to provide a white solid (83%). MS (ESI) 599.18, 597.18 (M+H+).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:20][S:21]SC.CCOCC>C1COCC1>[Cl:6][C:7]1[C:8]([S:21][CH3:20])=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CSSC
Reactant: CC1(C)COC(c2cccc(Cl)c2)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSc1c(Cl)cccc1C1=NC(C)(C)CO1
Temperature: -65 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
n-Butyllithium (2.5M in hexane, 4.2 ml) was added to a solution of 2-(3-chlorophenyl)-4,4-dimethyloxazoline (2 g) in THF while maintaining the temperature below -45° C. The mixture was stirred at -65° C. for 3 hours. Dimethyl disulphide (1.0 g) was added and the mixture was stirred at -65° C. for 2.5 hours and allowed to warm to room temperature. Ether was added and the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-(3-chloro-2-methylsulphenylphenyl)-4,4-dimethyloxazoline (2.35 g) as a yellow oil NMR (CDCl3) 2.0(s,6H) 3.0(s,3H) 4.65(s,2H) 7.5-8.1(m,3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[C:16]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[CH:15]=2)=[CH:9][CH:8]=1)=[N+]=[N-]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[C:16]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[CH:15]=2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=NCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Agent: [Pd]
Solvent: CCO
Product: NCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
229 mg of 6-{[4-(3-azidopropyl)phenyl]amino}-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 200) was dissolved in 30 mL of ethanol, to which 46 mg of 10% palladium carbon was added, and stirred under a hydrogen atmosphere at room temperature for 1 hour. The 10% palladium carbon was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1 to chloroform:ammonia methanol=10:1) to obtain 161 mg (75%) of the title compound as a white crystalline powder.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.[CH3:26][C:27]1([C:30]([O:32]C)=[O:31])[O:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[OH:29][C:27]([CH3:28])([CH2:26][N:12]1[CH:11]=[C:10]([C:8]2[CH:7]=[C:6]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=3)[CH:5]=[C:4]([CH3:3])[CH:9]=2)[CH:14]=[N:13]1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)C1(C)CO1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(C)(O)C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (23.5 mg, 0.59 mmol) at 0° C. was added to an oven-dried vial containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (75 mg, 0.24 mmol) in DMF (0.8 mL). The mixture was stirred for 10 minutes, and then methyl 2-methylglycidate (0.03 mL, 0.24 mmol) was added. The reaction was warmed to room temperature and stirred overnight, followed by subsequent heating to 70° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with water (3×), then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (45 to 85% ACN/water with 0.1% TFA modifier) to afford racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid. MS ESI calcd. for C19H18F3N5O3 [M+H]+ 422. found 422.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([N:10]2[CH:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.C([N-]C(C)C)(C)C.[Li+].Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCCC1>[C:40]([O:39][C:37](=[O:38])[CH2:36][C@H:7]([CH2:6][C:4]1[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[S:1][CH:5]=1)[C:8]([N:10]1[CH:14]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][O:12][C:11]1=[O:22])=[O:9])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCc1csc2ccccc12)N1C(=O)OCC1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](Cc1csc2ccccc12)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-benzo[b]thiophen-3-yl-propionyl)-4-benzyl-oxazolidin-2-one (3.35 g, 9.18 mmol) in 100 mL anhydrous tetrahydrofuran at −78° C. was added lithium diisopropyl amide in tetrahydrofuran (6.1 mL, 11.01 mmol) and the reaction mixture was stirred for 30 min Following addition of t-butyl bromoacetate (1.62 mL, 11.01 mmol) at −78° C., the mixture was stirred overnight while it was allowed to warm to room temperature. The solvent was evaporated and the residue diluted with ethyl acetate. The organic layer was washed with water (3×100 mL), dried, filtered, and concentrated to give the crude product. The title product was obtained by filtration through a pad of silica, eluting with methylene chloride (49%).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[S:13].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C>>[OH:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([CH3:18])[C:15](=[O:16])[N:14]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]1=[S:13]
Reactant: Cc1c(-c2ccccc2)n(COCCO)c(=S)[nH]c1=O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)n(COCCO)c(=S)n(Cc2ccccc2)c1=O
Yield: 30 %

Procedure:
To 2 ml of dimethylformamide 0.62 g (2.0 mmol) of 1-[(2-hydroxyethoxy)methyl]-6-penylthiothymine, 0.26 ml (2.2 mmol) of benzyl bromide and 0.38 ml (2.2 mmol) of ethyldiisopropylamine were added and allowed to react for 5 days at room temperature under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was adsorbed on a silica gel column and eluted with 1% methano/chloroform to obtain 0.24 g of the target compound (Yield: 30%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[O:5][CH:4]([CH2:14][CH2:15][C:16]#[N:17])[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[S:27])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[O:5][CH:4]([CH2:14][CH2:15][C:16]#[N:17])[CH2:3]1
Reactant: CN1CC(CCC#N)Oc2ncccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN1CC(CCC#N)Oc2ncccc2C1=S
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a solution of 11.0 g (0.04 mole) of 2,3,4,5-tetrahydro-4-methyl-5-oxopyrido[3,2-f][1,4]-oxazepine-2-propanenitrile in 175 ml toluene was added 10.5 g (0.026 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. The reaction mixture was heated to reflux for 2 hr with vigorous mechanical stirring. Another 3.0 g (0.007 mole) of 2,4 bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide was added and heating continued for 1 hr additional. The reaction mixture was allowed to cool and stand overnight at room temperature. Toluene was removed by rotary evaporation (90° C., water aspirator) and the residue taken up in 200 ml chloroform. This was washed with 2×50 ml 2M aqueous potassium hydroxide and concentrated by rotary evaporator (90° C., water aspirator). Crystallization ensued upon cooling. Recrystallization from isopropyl alcohol afforded 1.60 g (13.8%) product, m.p. 155°-56° C.
Reaction SMILES: [H-].[K+].[CH2:3]([N:6]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH3:9])[CH2:4][CH3:5].Br[CH2:22][C:23]1[C:31]2[N:30]=[CH:29][N:28]([C:32]([O-:34])=[O:33])[C:27]=2[CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:22][C:23]([CH3:31])([O:34][C:32]([N:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][C:10]([N:6]([CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH3:5])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:31]=2[N:30]=[CH:29]1)=[O:33])[CH3:24]
Reactant: O=C([O-])n1cnc2c(CBr)cccc21
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(CCC)C(Cc1cccc2c1ncn2C(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Reaction time: 0.08 h
Yield: 161.4 %

Procedure:
Potassium hydride (3.3 g of 40% oil suspension, washed with ether to remove oil, 0.03 mol) was added to a stirred solution of diethyl (dipropylamino)-malonate (10.2 g, 0.039 mol) in dry THF (100 mL). After 5 minutes, t-butyl, 4-(bromomethyl)-1H-benzimidazole-1-carboxylate (6.22 g, 0.02 mol) was added and the solution was refluxed for 6 hours. The solvent was removed under reduced pressure and the residual oil was partitioned between ethyl acetate and water. After evaporation of the ethyl acetate, the crude product was chromatographed on silica gel using ethyl acetate:hexane as the eluant to give 7.9 g of diethyl {((1,1-dimethylethoxycarbonyl)-1H-benzimidazole-4-yl)methyl}(dipropylamino)-propanedioate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)cc1
Temperature: 140 °C
Yield: 31.6 %

Procedure:
A mixture of 4-chloroaniline (2 g, 15.7 mmol), sodium bicarbonate (1.58 g, 18.8 mmol) and ethyl 2-bromo-2-methylpropanoate (6.12 g, 31.4 mmol) was heated at 140° C. in microwave reactor for 2 h. The reaction was cooled to rt and filtered. The filtrate was concentrated and purified by flash column chromatography using 0-40% EtOAc in heptanes as eluent. The product containing fractions were collected, concentrated, and dried under high vacuum overnight to give ethyl 2-(4-chlorophenylamino)-2-methylpropanoate (1.2 g, 32% yield) as an brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].[Na]>C(=O)(OC)OC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cc1ccccc1Oc1cccc(OC)c1
Agent: [Na]
Solvent: COC(=O)OC
Product: COC(=O)C(C(=O)OC)c1ccccc1Oc1cccc(OC)c1

Procedure:
Methyl 2-(3-methoxyphenoxy)phenylacetate (6.81 g) was dissolved in 11 mL of dimethyl carbonate and 600 mg of sodium was added. The mixture was heated at reflux for 10 h, then cooled. The reaction mixture was quenched with water, acidified with concentrated aqueous HCl and extracted with dichloromethane. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give an oil. The desired material was separated from unreacted starting material by flash chromatography (4:1 hexane: ethyl acetate as eluant) to yield after concentration, 3.54 g (43%) of the title compound of Step B. 1H NMR (CDCl3): δ7.46(dd,J=1.5,7.5Hz,1H), 7.29 (t,J=8Hz,1H), 7.2 (m,2H), 6.92 (d,J=8Hz,1H), 6.65 (td, J=1.5,7.5Hz,1H), 6.5 (m,2H), 5.14 (s,1H), 3.77 (s,3H), 3.73 (s,6H).
Reaction SMILES: [OH:1][CH:2]([CH2:22][N:23]([CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[C:37]1([CH:43]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:47]1([CH:43]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:44]([O:1][CH:2]([CH2:22][N:23]([CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12]3)=[CH:7][CH:6]=2)=[O:45])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCN(CC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(CC(COc1ccc2c(=O)cc(-c3ccccc3)oc2c1)OC(=O)C(c1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Yield: 76 %

Procedure:
A mixture of 7-[2-hydroxy-3-[N-(benzyloxycarbonyl)-propylamino]propoxy]flavone in crude form (5.09 g, 11 mmol), diphenylacetyl chloride (10.20 g, 44 mmol), and triethylamine (19.0 ml, 136 mmol) in toluene (65 ml) was refluxed under nitrogen for 18 hr. Toluene was removed by evaporation and the oily residue was dissolved in chloroform, washed twice with saturated NaHCO3 and once with water, and then dried (K2CO3). The dried solution, upon evaporation, gave a brown oil which was purified by HPLC (Water Associates PrepLC/Systems 500) using 3% acetone/CH2Cl2 that contained a small amount of NH4OH. A tan syrup of the title compound was obtained; 5.57 g (76% yield).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([NH:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:18])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:26]([NH:36][C:37](=[N:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])SC)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C=O)C>[C:41]([NH:40][C:37](=[N:36][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:14]([NH:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:18])=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-N2 -(Boc)-(R)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide (11.47 g; 0.33 mmol; from step (a) above) in DMF (50 mL) was added N,N'-bis(Cbz)-S-methylisothiourea (11.8 g; 0.33 mmol). The solution was stirred overnight at room temperature followed by removal of the solvent under reduced pressure. The resultant oil was chromatographed on a plug of silica gel (7.5 cm×12.5 cm) eluting first with CH2Cl2 (800 mL) to remove the higher Rf impurities. The eluent was switched to EtOAc (600 mL) to elute the sub-title compound as a white foam (14.67 g).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][C:6]([NH2:8])=[NH:7].CC[O-].[Na+].[CH3:13][S:14][C:15](SC)=[C:16]1[C:25](=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][O:17]1.O>CCO>[CH3:13][S:14][C:15]1[C:16]2[O:17][CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: N=C(N)N
Reactant: CSC(SC)=C1OCc2ccccc2C1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CSc1nc(N)nc2c1OCc1ccccc1-2

Procedure:
A solution of guanidine nitrate (1.5 g, 12 mmol) in EtOH (9 mL) was treated with 3 mL of 1 M EtONa in EtOH, refluxed for 15 minutes, cooled, treated with a solution of Example 41A in EtOH (5 mL), heated at reflux overnight, cooled, treated with water (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of CH2Cl2:EtOAc (1:0 and 20:1) to provide the title compound. 1H NMR (DMSO-d6) δ 2.46 (s, 3H), 5.18 (s, 2H), 6.31 (s, 2H), 7.29 (m, 1H), 7.42-7.51 (m, 2H), 7.96 (m, 1H). MS (M+H)+ m/z 246.