Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:24]=2[C:25]([OH:27])=O)=[CH:18][CH:17]=1.N>P(=O)(O)(O)O>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:22][C:23]3[C:24](=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)[C:25](=[O:27])[C:20]=2[CH:21]=1
Reactant: Nc1ccc(Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Agent: N
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Nc1ccc2[nH]c3ccc([N+](=O)[O-])cc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
See Korolev et al., 1976. Polyphosphoric acid was freshly prepared by slowly adding, with stirring, 85% orthophosphoric acid (360 mL) to phosphorus pentoxide (600 g). The mixture was then heated on a steam bath with stirring until a clear viscous liquid was obtained. 2-(-4-amino-phenylamino)-5-nitrobenzoic acid 10 (107.76 g, 0.394 mol) was added with stirring over the course of 5 min. Heating on the steam bath was continued for 6 hr, the mixture being stirred occasionally. Whilst still hot, the mixture was poured into 4 L of ice-water, stirred for 30 min and allowed to stand overnight. The mixture was adjusted to pH 8.0 by the addition of 0.88 s.g. aqueous ammonia, chilled for 2 hr, and the crude product collected on a glass sinter. It was washed with dilute ammonia (1% 0.88 s.g. aqueous ammonia in water, 250 mL) followed by water (3×250 mL), ice-cold ethanol (2×250 mL), dry ether (2×250 mL) and finally hexane (250 mL). The product, 11, was dried over P2O5 under vacuum to yield a red-brown solid (97.04 g, 96%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[C:18]3[C:24]#[N:25])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].C[Si]([N:32]=[C:33]=[O:34])(C)C>O1CCOCC1>[C:24]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:33]([NH2:32])=[O:34])=[CH:27][CH:26]=3)[CH:16]=2)[NH:20][CH:19]=1)#[N:25]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Solvent: C1COCCO1
Product: CC(C)(CNC(N)=O)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of 4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide (90 mg, 0.25 mmol) (reference example 105) in 1,4-dioxane (1 ml) was added trimethylsilyl isocyanate (68 μL, 0.50 mmol). The resulting mixture is stirred for 16 h. The precipitated solids are collected by vacuum filtration, washed with a small volume of CH2Cl2 and dried under high vacuum to give 99 mg of product. MS (ion spray) m/z 404 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([OH:27])=O)[C:21]([OH:28])=[CH:20][C:19]=1[CH2:29][C:30]([OH:32])=O>CCOC(C)=O.CCCCCC>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:30](=[O:32])[CH2:29][C:19]1[CH:20]=[C:21]([OH:28])[C:22]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:23][C:18]=1[OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)Cc1cc(O)c(CC(=O)O)cc1O
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cc(O)c(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)cc1O
Yield: 23.9 %

Procedure:
Using General Procedure A with 10.7 g (44.2 mmol) D-Proline benzyl ester hydrochloride and 5.0 g (22.1 mmol) 2,5-dihydroxy-1,4-phenylenediacetic acid afforded, after flash chromatography (gradient: 70-100% EtOAc/hexane), 3.17 g (24%) of the title compound as a colorless foam. MS m/e (%): 601 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:20]1[NH:28][C:27]2[C:22](=[N:23][CH:24]=[N:25][CH:26]=2)[N:21]=1>C(OCC)(=O)C.O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([S:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:20]1[NH:28][C:27]2[C:22](=[N:23][CH:24]=[N:25][CH:26]=2)[N:21]=1
Reactant: C1COCCN1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2ncncc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(S(=O)(=O)N2CCOCC2)ccc1-c1nc2ncncc2[nH]1
Temperature: 80 °C

Procedure:
An amount of 0.8 ml of morpholine was dissolved in a two-phase mixture of 40 ml of ethyl acetate and 40 ml of water. Then, 1 gm of crude 8-(2'-methoxy-4'-chlorosulfonylphenyl)-purine hydrochloride was added thereto in batches, under vigorous stirring, and the resulting mixture was heated to 80° C. for two hours. The reaction mixture was concentrated down to one-third of the volume, and the crystals precipitated were subjected to suction filtration and washed with water.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:33][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCC1
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC2CCC2)C1(C)C

Procedure:
The product from Example 173 and cyclobutylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.00 (s, 3H), 0.44 (t, J=7.3 Hz, 3H), 0.74 (s, 3H), 0.77 (s, 3H), 0.80-0.98 (m, 3H), 1.11 (s, 9H), 1.11-1.21 (m, 5H), 1.32-1.57 (m, 3H), 1.62-1.72 (m, 2H), 2.13-2.21 (m, 3H), 2.26-2.36 (m, 1H), 3.67-3.80 (m, 1H), 7.32 (d, J=7.7 Hz, 1H), 8.04 (s, 1H). (ESI+) m/z 448 (M+H)+. Anal. calcd. for C25H41N3O2S: C, 67.07; H, 9.23; N, 9.39. Found: C, 66.48; H, 9.40; N, 9.24.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)c1ccc2occ(-c3ccc(OC(F)(F)F)cc3)c2c1
Yield: 74 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(trifluoromethoxy)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 74%) was obtained as colorless crystals.
Reaction SMILES: I[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[CH:7][C:8]=3[O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)cc1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)sc23)cc1

Procedure:
This compound can be prepared from 4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 72, Step A) and phenylboronic acid using the procedure described for Example 94, Step A.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:44][C:43]1[CH:42]=[CH:41][C:40]([O:39][CH2:38][CH2:37][CH2:36][Cl:35])=[CH:47][CH:46]=1)[C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCOc1ccc(CBr)cc1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Reaction time: 0.33 h

Procedure:
A solution consisting of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole No. 7 (6.5 g, 15.5 mmol) in DMF (60 mL) was cooled to 0° C. and treated with addition of sodium hydride (0.68 g, 17.0 mmol) and stirred for 20 minutes. A solution of 4-(3-chloropropoxy)-benzyl bromide No. 163 in DMF (10 mL) was then added slowly. The reaction was allowed to come to rt and stirred for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water, brine and dried over magnesium sulfate and concentrated. The concentrate was treated with methanol and 5 g of the desired product precipitated as a white solid with a melting point of 130-132° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:18]
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)C1CCNCC1

Procedure:
This compound was prepared similarly to Preparation C starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and N-methylbenzylamine, and was used directly in Example 10. This intermediate was characterised as the hydrochloride salt, m.p. 175°-176°.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[OH:25])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:14]2[CH:13]=[CH:12][C:11]([OH:25])=[C:10]([CH:15]=2)[CH2:9][P:4](=[O:3])([OH:5])[OH:8])=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(Cc2ccc(O)c(CP(=O)(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.8 %

Procedure:
To a solution of [5-(4-ethylbenzyl)-2-hydroxybenzyl]phosphonic acid diethylester (0.40 g) in dichloromethane (7.8 mL) was added bromotrimethylsilane (0.8 mL) at 0° C., and the reaction mixture was stirred for 17 hr at room temperature. Methanol (1.1 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate-n-hexane to give the title compound (0.29 g) as a colorless crystal.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[N:10]1[CH:15]=[CH:14][C:13]([C:2]2[O:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: OB(O)c1ccncc1
Product: O=C(O)c1coc(-c2ccncc2)c1

Procedure:
Using the procedure outlined in Description 29, the title compound was prepared from 2-bromo-furan-4-carboxylic acid (S. W. En, M. C. Yuen, H. N. C. Wong, Tetrahedron, 1996, 52(37), 12137) and 4-pyridylboronic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][C@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][C@H:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCC[C@H]1CCOC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CC[C@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3R)-3-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: CS[C:3]1[C:12]2[N:13]=[CH:14][NH:15][C:11]=2[C:10]2[N:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[ClH:24].BrC1C=C(C=CC=1)N>CN1CCCC1=O>[ClH:24].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:12]2[N:13]=[CH:14][NH:15][C:11]=2[C:10]2[N:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1cc2cncnc2c2[nH]cnc12
Agent: Cl
Solvent: CN1CCCC1=O
Product: Brc1cccc(Nc2cc3cncnc3c3[nH]cnc23)c1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
A mixture of 4-methylthioimidazo[4,5-h]quinazoline (0.216 g, 1 mmol), 3-bromoaniline (0.25 g, 1.5 mmol), and 3-bromoaniline hydrochloride (0.31 g, 1.5 mmol) in N-methylpyrrolidone (50 mL) is heated 120° C. for 2 h. The solvent is removed under vacuum and the residue is triturated with EtOH to give a solid which is recrystallized from MeOH to give 4-(3-bromoanilino)imidazo[4,5-h]quinazoline hydrochloride (0.23 g, 61%). 1H NMR (DMSO) δ11.11 (1H, brs), 8.93 (2H, s), 8.66 (1H, d, J=9.0 Hz), 8.11 (1H, brs), 8.07 (1H, d, J=9.0 Hz), 7.83 (1N, brd, J=6.8 Hz), 7.50-7.40 (2H,m).
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:3]=1[F:28].Cl.[N:30]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[F:28][C:3]1[C:2]2[N:1]=[N:30][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (2.50 g, 5.99 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO2 (0.45 g, 6.58 mmol) in water (10 mL) was added dropwisely at 0° C. in 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO3 (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.82 g, 90.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.83 (s, 1H), 8.59 (d, 1H), 7.45 (m, 1H), 7.24 (m, 1H), 6.95 (m, 2H), 4.03 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][NH:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CCNC=C2C(=O)Nc3cc(OC)c(OC)cc32)cc1OC

Procedure:
5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 6.00 g. of 2(3,4-dimethoxyphenyl)ethylamine and 2.20 acetic acid in 40 ml. benzene was reacted as described in Example 5 to give 6.30 g. product, m.p. 164°-166° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:17]3=[O:41])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:42].[CH:43]1[C:48](O)=[CH:47][CH:46]=[C:45]([CH3:50])[CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(N=NC(OCC)=O)=O>C(OCC)(=O)C.C1COCC1>[CH3:50][C:45]1[CH:46]=[CH:47][C:48]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH2:15][CH:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:41])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:42])=[CH:43][CH:44]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C1CCc2c(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cccc2N1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCN2C(=O)CCc3c(CC4SC(=O)NC4=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A THF solution (2 ml) of 100 mg (0.18 mmol) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-trityl thiazolidine-2,4-dione, 0.0363 ml (0.347 mmol) of p-cresol, and 91.1 mg (0.35 mmol) of triphenylphosphine was cooled with ice. 0.158 ml of azodicarboxylic acid diethyl (2.2 M toluene solution) was added to the solution in an argon atmosphere. The mixture was stirred at room temperature for two hours, and ethyl acetate was added to the reaction liquid. After washing with water, the organic layer was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, and 2 ml of a solution of 4N-hydrogen chloride/ethyl acetate was added to the residue. The mixture was stirred at room temperature overnight, and further stirred at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure and evaporated to dryness, giving 27.1 mg (34.4% yield) of 5-{1-[3-(4-methylphenoxy)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[OH:32]>>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:21]2[CH:20]=[CH:19][C:18]([OH:32])=[C:17]([O:16][CH3:15])[CH:22]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Clc1cncc(NCc2ccco2)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(NCc3ccco3)n2)ccc1O
Yield: 92 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-(2-furylmethyl)pyrazin-2-amine and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (92%).
Reaction SMILES: C(O)C.O[NH:5][C:6](=[NH:19])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)OCC[O:9]1.Cl>O>[C:13]1([C:8]2[O:9][N:5]=[C:6]([NH2:19])[CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C(CC1(c2ccccc2)OCCO1)NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)on1
Temperature: 90 °C
Yield: 33.2 %

Procedure:
Ethanol (125 mL) and H2O (25 mL) are added to N-hydroxy-2-(2-phenyl-1,3-dioxolan-2-yl)ethanimidamide (7 g, 32 mmol). The pH is adjusted to 1 with the addition concentrated HCl and the reaction mixture is heated at 90° C. for 2 h. The solvent is evaporated to dryness and the resulting residue is neutralized using phosphate buffer. The mixture is extracted with ethyl acetate and the combined organic phases are dried (Na2SO4) and concentrated in vacuo. The crude residue is purified over neutral alumina eluting with 30% ethyl acetate/hexane to afford the title compound as an off-white solid (1.7 g, 34%).
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reaction time: 8 h

Procedure:
1.41 parts of N-acetoacetyl-L-aspartic acid were dissolved in 25 parts by volume of acetic acid, and 5 parts by volume of acetic anhydride were added and the mixture was stirred overnight under nitrogen. Solvent was removed under vacuum at 40°-45° C. 50 parts by volume of acetic acid were added and the evaporation repeated to form N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)=[O:4].[Br:15]Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:15])[CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)=[O:4]
Reactant: COC(=O)c1cccc2c1SCCC2
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c1SCCC2
Yield: 82.2 %

Procedure:
A solution of methylthiochroman-8 carboxylate (0.300 g, 1.44 mmol) (D6a) in dichloromethane (20 ml) was treated with bromine (0.106 ml, 2.07 mmol) and the reaction mixture left at room temperature. After 4 days the reaction mixture was washed with sodium metabisulphile solution. The organic layer was then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a colourless oil (0.340 g, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.BrCCBr.[Mg].Br[CH2:17][C:18]([CH3:20])=[CH2:19]>O1CCCC1>[CH3:19][C:18](=[CH2:17])[CH2:20][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2c(c1)CCO2
Reactant: C=C(C)CBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(C)Cc1ccc2c(c1)CCO2
Temperature: 30 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2,3-dihydrobenzofuran (50 grams, 0.251 mole), and 1,2-dibromoethane (2.2 ml) in tetrahydrofuran (250 ml) was added dropwise to a stirred suspension of magnesium turnings (7.5 grams, 0.31 gram-atoms) in tetrahydrofuran (50 ml) over a period of 45 minutes. During the addition the reaction temperature was maintained at 30° C. The solution was cooled in an ice-bath and 3-bromo-2-methylpropene was added all at once. After stirring overnight, the reaction was quenched with cold 2% hydrochloric acid and the mixture was extracted with ether. Evaporation of solvent gave 5-(2-methylallyl)-2,3-dihydrobenzofuran as an oil (43.4 grams, 99%). M+ 174.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[C:30]2[C:25](=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1.Cl.ClC1C2C(=C(S(Cl)(=O)=O)C=CC=2)C=CN=1>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]=[CH:23][N:22]=[C:21]2[Cl:20])(=[O:33])=[O:32])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
According to the method of Example 1, Step A, a solution of N-(3-aminopropyl)carbamic acid tert-butyl ester (383 mg) and triethylamine (335 μl) in dichloromethane (3 ml) was added with a solution of (1-chloro-5-isoquinolyl)sulfonyl chloride (524 mg, prepared from (1-chloro-5-isoquinolyl)sulfonyl chloride hydrochloride according to the method of Japanese Patent Unexamined Publication (Kokai) No. 63-2980) in dichloromethane (3 ml) with stirring and ice cooling and stirred at room temperature for 20 hours. The reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate twice and with saturated brine. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries), and then the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (640 mg).