Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[O:8][CH:7]=1.[C:17]([Li])(C)(C)C.IC>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17]
Reactant: [Li]C(C)(C)C
Reactant: COc1ccc2c(C3OCCO3)coc2c1
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(C3OCCO3)c(C)oc2c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
3-(1,3-Dioxolan-2-yl)-6-methoxybenzofuran (0.144 g, 0.65 mmol) was dissolved in THF (5 mL) at −30 to −20° C. To this solution was added dropwise tert-butyllithium (15% in pentane, 0.56 mL, 1.31 mmol). The reaction mixture was continuously stirred at −30° C. for 30 min and then allowed to warm to 0° C. and stir for another 20 min. The reaction mixture was cooled to −30° C. again and iodomethane (0.138 g, 0.98 mmol) was added dropwise. After stirring at −30° C. for another 1 h, it was allowed to warm to room temperature overnight. After the solvent was removed under reduced pressure, the residue was dissolved in EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure to provide 3-[1,3]dioxolan-2-yl-6-methoxy-2-methyl-benzofuran.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6]Br)[CH3:2].[I:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:18]=[CH:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14](=[O:23])[C:13]=2[CH:24]=1>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:14]1([OH:23])[C:13]2[CH:24]=[C:9]([I:8])[CH:10]=[CH:11][C:12]=2[CH:18]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2)[CH3:2]
Reactant: CCOCCCBr
Reactant: O=c1c2ccccc2ccc2ccc(I)cc12
Solvent: C1CCOC1
Product: CCOCCCC1(O)c2ccccc2C=Cc2ccc(I)cc21

Procedure:
3-Ethoxypropyl bromide (7.5 g., 0.045 mole) is converted to the Grignard reagent using standard procedures (see above). To this solution (ca 60 ml.), stirred in an ice bath, is added dropwise a solution of 10 g. (0.030 mole) of 3-iodo-5H-dibenzo[a,d]cyclohepten-5-one in 30 ml. of dry THF. The mixture is stirred for 5 minutes and concentrated in vacuo. The residue is treated with saturated ammonium chloride solution and extracted three times with ether. The ether layer is washed once with water, dried over sodium sulfate, and evaporated in vacuo to an orange solid, m.p. 95°-105° (12.0 g., 95%).
Reaction SMILES: [N+:1]([O-:16])([O:3][C@@H:4]([C@H:6]([O:12][N+:13]([O-:15])=[O:14])[CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH3:5])=[O:2].Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[C:18](=[O:19])([O:20][CH:21]([Cl:23])[CH3:22])[O:10][CH2:9][CH2:8][CH:7]([CH3:11])[C@@H:6]([O:12][N+:13]([O-:15])=[O:14])[C@H:4]([O:3][N+:1]([O-:16])=[O:2])[CH3:5]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(CCO)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,3R)-6-hydroxy-4-methylhexane-2,3-diyl dinitrate (Intermediate 2, 0.78 g, 3.26 mmol) in CH2Cl2 (15 mL) cooled at 0° C., 1-chloroethyl chloroformate (0.355 mL, 3.26 mmol) was added. Then a solution of Pyridine (0.263 mL, 3.26 mmol) was added dropwise. The solution was stirred at room temperature overnight. Then it was diluted with CH2Cl2 (25 mL) and washed with HCl 1 N (2×15 mL), a saturated solution of NaHCO3 (15 mL) and brine. The organic layer was dried over Na2SO4 and concentrated affording the title compound as colorless oil.
Reaction SMILES: F[C:2]1[C:20]2[C:19](=[O:21])[C:18]([C:22]([OH:24])=[O:23])=[CH:17][N:7]3[C@@H:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:3]=1[F:35].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>CS(C)=O>[F:35][C:3]1[C:4]([NH:25][CH2:26][CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:5]2[O:10][CH2:9][C@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:7]3[CH:17]=[C:18]([C:22]([OH:24])=[O:23])[C:19](=[O:21])[C:20]([C:2]=1[NH:43][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=1)=[C:6]23
Reactant: O=C(O)c1cn2c3c(c(NCCNc4ccccn4)c(F)c(F)c3c1=O)OC[C@@H]2c1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@@H](c2ccccc2)CO3)cc1
Temperature: 0 °C
Yield: 56.9 %

Procedure:
A solution of (S)-8,9-difluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (560 mg, 1.15 mmol) and 4-methoxybenzylamine (520 μL, 5.86 mmol) in DMSO (5 mL) was stirred at 150° C. for 2 h. The reaction mixture was added portionwise at 0° C. to ice-water and the resulting precipitate was combined by filtration, washed with water. The cake washed with EtOH, collected by filtration and then dried to give (S)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (390 mg, 57%) as a pale yellow solid.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH3:9][C:10]1[C:22]2[C:21]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([OH:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc2c1C(=O)c1ccccc1-2
Reactant: Cl[Mg]c1ccccc1
Product: Cc1cccc2c1C(O)(c1ccccc1)c1ccccc1-2

Procedure:
from phenylmagnesium chloride and 1-methyl-9-fluorenone;
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:10])([F:9])[F:8])[C@@H:3]1[C:12](O)=[O:13].S(Cl)([Cl:18])=O>>[CH3:1][C:2]1([CH3:15])[C@H:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:10])([F:9])[F:8])[C@@H:3]1[C:12]([Cl:18])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
10 g of cis-2,2-dimethyl-3-(2'-chloro-3',3',3'-trifluoropropenyl)-cyclopropanecarboxylic acid were dissolved in 50 ml of thionyl chloride and the solution was heated to the boil for one hour. After distilling off the excess thionyl chloride, the residue was distilled under a high vacuum. Cis-2,2-dimethyl-3-(2'-chloro-3',3',3'-trifluoropropenyl)-cyclopropanecarboxylic acid chloride of boiling point 52°-54° C./0.9 mm Hg and nD20 : 1.4520 was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Cl:17])[C:9]=3[CH:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:43])[CH2:26][CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][C:41]#[N:42])OC5C=CC=CC=5)[CH2:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.[NH4+:44].[OH-]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Cl:17])[C:9]=3[CH:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:43])[CH2:26][CH:27]4[CH2:31][CH2:30][N:29]([C:32](=[NH:44])[NH:40][C:41]#[N:42])[CH2:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: N#CN=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#CNC(=N)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve the product of Example 7 in 2-propanol and add concentrated NH4OH. Stir the mixture at 25° C. for 24 h and then evaporate to dryness. Triturate the residue with Et2O (2×250 ml) and discard the ether. Chromatograph the resulting product on a silica gel column using 4% (10% concentrated NH4OH in CH3OH)--CH2Cl2 as the eluant to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[N:39][C:40]([NH:43][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7](=[O:23])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:41][CH:42]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 8.9 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-[6-(8-cyclopentyl-6-ethoxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140 g, 14.7%). 1H NMR δ(400 MHz, CDCl3) 8.59 (s, 1H), 8.26 (d, J=9.3 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.6 (t, J=1.5 Hz, 1H), 7.38 (dd, J=2.7, 9.0 Hz, 1H), 5.89 (m, 1H), 4.55 (d, J=1.2 Hz, 1H), 3.66 (q, J=7.1 Hz, 2H), 3.60 (m, 4H), 3.11 (m, 4H), 2.34 (m, 2H), 2.07 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31](O)(=[O:33])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([NH:35][S:31]([C:5]2[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=2)/[CH:7]=[CH:8]/[C:9]2[N:17]([CH3:18])[C:16]3[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=2)(=[O:32])=[O:33])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Reactant: Nc1ccccc1
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)Nc3ccccc3)n2C)n(CCC)c1=O
Yield: 23.5 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 1.85 ml (20.3 mmol) of aniline. The resulting crude crystals were recrystallized from toluene to give 261 mg (yield 23%) of Compound 10 as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reaction time: 1.5 h

Procedure:
Ethyl 5-chloroindole-2-carboxylate (1.4 g) was dissolved in N,N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) and benzyl chloride (2.4 ml) were added. The mixture was heated and stirred for 1.5 hours on a hot bath controlled to 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was poured into ice water and extracted with ethyl acetate. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatagraphy on silica gel (ethyl acetate:hexane=1:19) and crystallized from diethyl ether-hexane to obtain the title compound (1.6 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[O:32])[NH:24][C:23]3[CH:33]=[CH:34][CH:35]=[N:36][C:22]2=3)=[O:20])[CH2:14][CH2:13]1.[C:37]1([N:46]=[C:47]=[S:48])[CH:42]=[CH:41][CH:40]=[C:39]([N:43]=[C:44]=[S:45])[CH:38]=1.C(OCC)(=O)C>CN(C=O)C>[N:43]([C:39]1[CH:38]=[C:37]([NH:46][C:47]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25](=[O:32])[NH:24][C:23]4[CH:33]=[CH:34][CH:35]=[N:36][C:22]3=4)=[O:20])[CH2:14][CH2:13]2)=[S:48])[CH:42]=[CH:41][CH:40]=1)=[C:44]=[S:45]
Reactant: NCCCCCCCCCCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Reactant: S=C=Nc1cccc(N=C=S)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCCCCCCCCNC(=S)Nc3cccc(N=C=S)c3)CC2)c2ccccc21
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
5,11-Dihydro-11-[(4-[10-aminodecyl]-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one (2.8 mg, 5.7 μmol) was dissolved in 0.2 mL DMF and treated with 1,3-phenylenediisothiocyanate (6 mg, 31 μmol). After 0.5 h, ethyl acetate (1 mL) and petroleum ether (3 mL) were added, and the cloudy mixture was stored at 4° C. overnight. The supernatant was decanted from the oily residue. The residue solidified upon trituration with dry ether to give 2.0 mg (51% yield) of pure product (Rf =0.35, silica, chloroform:methanol:acetic acid, 85:10:5, by volume). FAB-MS spectrum showed a parent ion peak at 685 m/z (m+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH:16][C:31](=[O:33])[CH3:32])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanamine (500 mg, 1.56 mmol) in DCM (5 mL) was added pyridine (185 mg, 2.3 mmol). After stirring for 5 min at RT, a solution of acetyl chloride (147.2 mg, 1.88 mmol) in DCM (0.5 mL) was added into the reaction mixture, which was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated aq NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with ether to yield N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide (500 mg). 1H NMR (CDCl3, Free base) δ (ppm): 8.42 (d, 2H), 7.25 (s, 1H), 7.15 (d, 1H), 6.92 (d, 2H), 6.9 (d, 1H), 6.2 (d, 1H), 5.3 (q, 1H), 4.4 (dd, 1H), 4.25 (dd, 1H), 3.58 (dd, 2H), 2.6 (m, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 2.3 (m, 2H), 2.03 (s, 3H). Separation by chiral HPLC provided enantiomers II-1a-b.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:26][CH2:27][CH2:28][OH:29].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:8]([C:9]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:10])=[CH:7][C:6]=1[O:26][CH2:27][CH2:28][OH:29]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(=O)O)cc(OCCO)c2Oc2cc(OC)ccc2Cl)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(=O)Nc3ccccc3)cc(OCCO)c2Oc2cc(OC)ccc2Cl)cc1

Procedure:
Analogously to Example 74, by condensing 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonylamino)-benzoic acid with aniline there was obtained 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonylamino)-N-phenyl-benzamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[CH:11]([NH:14][C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])=[O:16])([CH3:13])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a stirred suspension of 5.0 g (37.6 mmole) of 2-oxindole in 50 ml of toluene was added 8.0 g (94.0 mmole) of isopropyl isocyanate, and the mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool and then it was stirred at room temperature overnight. The solvent was removed by evaporation in vacuo, and the residue was dissolved in hot cyclohexane. The solution was allowed to cool and the solid was collected by filtration, giving 7.0 g of the title compound, mp 84°-85.5° C., as pink crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[C:33]([F:32])([F:44])[F:45])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4C(F)(F)F)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-(trifluoromethyl)-benzenesulfonyl chloride. Purity (ELSD, based on MW=629.6)=90%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[C:16]([CH:17]2[CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][C:12]=1[Br:20])(=O)C.O.Cl>CO>[Br:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]2[CH2:18][CH2:19]2)[C:11]=1[OH:10]
Reactant: CC(=O)Oc1c(Br)cccc1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1c(Br)cccc1C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
Potassium carbonate (276 mg, 2.00 mmol) was added to a solution of 2-bromo-6-cyclopropylphenyl acetate (316 mg, purity: 80%, 1.00 mmol) in methanol (2 ml), and the mixture was stirred at room temperature for 4 hours. After water (15 ml) and 4M hydrochloric acid (15 ml) were added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was combined, washed with a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated to obtain a pale brown oil. This oil was purified by preparative thin layer chromatography (manufactured by Merck Co., Ltd, 1.05744, use of two sheets, development by hexane:ethyl acetate=30:1) to obtain 118 mg of 2-bromo-6-cyclopropylphenol.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=2)=[N:15][CH:16]=1>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:22]=2)=[N:15][CH:16]=1
Reactant: Oc1ccccc1
Reactant: ClCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnc(Nc2nc(COc3ccccc3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
Phenol (0.0356 g, 0.378 mmol) was dissolved in 3 mL THF at ambient temperature. NaH (0.00907 g, 0.378 mmol) was added and the mixture stirred for 30 minutes at ambient temperature. Solid N-(5-Bromo-3-phenoxypyridin-2-yl)-4-(chloromethyl)thiazol-2-amine (0.030 g, 0.0756 mmol) (Example 322) was then added to the reaction and the mixture was stirred at ambient temperature overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2, washed with water, dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (0.007 g, 20.4% yield) as the least polar of the two major products. 1H NMR (CDCl3) δ 5.07 (s, 2H), 6.88 (s, 1H), 6.96 (t, J=7.3 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.14 (d, J=2.0 Hz, 1H), 7.23-7.31 (m, 3H), 7.43 (t, J=8.0 Hz, 2H), 8.14 (d, J=2.0 Hz, 1H), 8.76 (br s, 1H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([CH3:29])[CH:12]=1)#[N:10].O>CN(C=O)C>[Br:8][C:21]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=2[CH3:29])[C:18]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCc1cccn1-c1ccc(C#N)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(Br)n1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (4.76 g, 1 equiv) was added portionwise to a solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate in DMF at 0° C. during 45 min. After addition, the mixture was stirred at room temperature for 30 min, then poured into water, and extracted with ethyl acetate for three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=15:1) to afford ethyl 3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:19]([N:21]([CH2:36][CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:20]>>[CH2:36]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: O=C1Cc2ccc(-c3cc(Cl)cc(Cl)c3)cc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4cc(Cl)cc(Cl)c4)ccc32)c1C
Yield: 44.6 %

Procedure:
6-(3,5-Dichlorophenyl)-1,3-dihydroindol-2-one (64 mg, 0.23 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (60 mg) to give 53 mg (44%) of the title compound as a light brown solid.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10](O)=[O:11])#[N:2].CCN(CC)CC.[H][H]>C1COCC1>[O:4]1[C:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[S:8][C:9]=2[C:10](=[O:11])[NH:2][CH2:1][CH2:3]1
Reactant: N#CCOc1c(C(=O)O)sc2ccccc12
Reactant: [H][H]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCOc2c1sc1ccccc21
Yield: 55 %

Procedure:
A mixture of the methyl ester of 3-(cyanomethoxy)benzo[b]thiophene-2-carboxylic acid (405 mg, 1.64 mmols) [J. Hetero. Chem., 12:1037 (1975)], 0.5 mL of Et3N and 0.50 g of RaCo in 50 mL of THF is heated at 100° C. under 1200 psi of hydrogen. The reaction mixture is concentrated in vacuo. Column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate provides 2,3-dihydro-[1]benzothieno[2,3-f]l,4-oxazepin-5(4H)-one in 55% yield, mp 244°-245° C.